Cellulose interpolymers and method of oxidation

ABSTRACT

This invention provides cellulose ester interpolymers, and methods of oxidizing cellulose interpolymers and cellulose ester interpolymers. The invention also provides routes to access carboxylated cellulose ester derivatives with high acid numbers wherein the carboxyl group is attached directly to the cellulose backbone by a carbon-carbon bond. Through functionalization of an intermediate aldehyde, the corresponding cationic or zwitterionic cellulose ester derivatives can also be accessed. The interpolymers of the present invention have a number of end-use applications, for example, as binder resins in various types of coating compositions and as drug delivery agents.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.12/975,440 filed on Dec. 22, 2010, now United States Publication No.2011-0098464; which is a divisional of U.S. application Ser. No.10/995,750 filed on Nov. 23, 2004, now U.S. Pat. No. 7,879,994; whichclaims benefit from the following provisional application under 35 USC119: U.S. Application Ser. No. 60/525,787, filed Nov. 28, 2003, nowexpired; all of which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention provides cellulose ester interpolymers, celluloseinterpolymers, and methods of oxidizing cellulose interpolymers andcellulose ester interpolymers.

BACKGROUND OF THE INVENTION

Cellulose esters are well known compounds (“Cellulose Derivatives”, BenP. Rouse, Kirk-Othmer Encyclopedia of Chemical Technology, vol 4, 1964,616-683). The most common cellulose esters are comprised of aliphaticC₂-C₄ substitutents. Examples of such cellulose esters include celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate propionate (CAP), and cellulose acetate butyrate(CAB). Examples of the utility of such cellulose esters can be found inProg. Polym. Sci. 2001, 26, 1605-1688. Cellulose esters are generallyprepared by first converting cellulose to a cellulose triester beforehydrolyzing the cellulose triester in an acidic aqueous media to thedesired degree of substitution (DS, the number of substitutents peranhydroglucose monomer). Aqueous acid catalyzed hydrolysis of cellulosetriacetate yields a random copolymer that can consist of 8 differentmonomers depending upon the final DS (Macromolecules 1991, 24, 3050).

Processes that provide non-random copolymers via hydrolysis of cellulosetriesters are known. Direct esterification to less than fullysubstituted cellulose esters is also known. Depending upon the precisereaction conditions, it is possible to obtain a non-random celluloseester by this type of process.

Recently, there have been accounts of attempts at the preparation ofregioselectively substituted cellulose derivatives. For the purposes ofthis invention, regioselective substitution means the exclusive orpreferential placement or removal of a substituent at the C2, C3, or C6hydroxyls of the anhydroglucose monomer of cellulose. Controlledplacement of the substitutent can lead to a homopolymer or a copolymerof cellulose with specific monomer content. That is, a cellulosederivative with a specific substitution pattern within theanhydroglucose monomer and a controlled sequence along the cellulosepolymer chain is obtained.

Prior methods leading to the formation of regioselective substitutedcellulose derivatives rely on the use of temporary protecting groups andeither requires the use of cellulose solvents so that the protectinggroup can be installed in a homogeneous reaction mixture or mercerizedcellulose that has sufficient reactivity.

The preparation of certain formate esters of carbohydrates andpolysaccharides is known. The isolated cellulose formates are typicallyused as unstable intermediates for subsequent reactions due to reportedinstability of the formate ester and reactivity toward other functionalgroups. As a result, the formation of mixed cellulose formatederivatives has received little attention, and few reports of theformation of a mixed cellulose formate esters exists. GB 568,439 (1945)teaches the preparation of cellulose acetate formate which is producedby mixing cellulose with an acetic and formic mixed anhydride in thepresence of a catalyst

Only a few classes of carboxylated cellulose esters are known. Oneexample of this class of cellulose ester derivatives is carboxymethylcellulose esters described for example in U.S. Pat. Nos. 5,668,273;5,792,856; and 5,994,530. These cellulose derivatives are celluloseether esters in which an intervening ether linkage attaches acarboxylate to the anhydroglucose units of the cellulose chain. Thesederivatives are formed by esterifying carboxymethyl cellulose (an ether)to the fully substituted carboxymethyl cellulose ester followed byhydrolysis to the desired ester DS. This class of carboxylated celluloseesters offers the advantage of a non-hydrolysable carboxylate linkage.The disadvantage is that the method of preparation is a two-step processrequiring the preparation and isolation of the carboxymethyl celluloseprior to esterification. Furthermore, one cannot obtain a consistent,homogeneous distribution of carboxymethyl substitutents along thecellulose backbone.

Another class of carboxylated cellulose esters is those in which thecarboxylate functionality is attached to the cellulose backbone via anester linkage. An example of this class is cellulose acetate phthalateand the like which are described in U.S. Pat. No. 3,489,743. In general,these cellulose ester derivatives are formed by first preparing aneutral, randomly substituted cellulose ester, e.g. a CA, with thedesired DS. In a second reaction, the carboxylate functionality isinstalled by treating the cellulose ester with an anhydride such asphthalic anhydride.

An additional class of carboxylated cellulose esters is those, whichresult from ozonolysis of cellulose esters in the solid state (Sand, I.D., Polymer Material Science Engineering, 1987, 57-63; U.S. Pat. No.4,590,265). Ozonolysis of cellulose ester provides a polymer thatcontains not only carboxylates but also aldehydes, ketone, and peroxidesas well. The process results in significant loss in polymer molecularweight and relatively low levels of oxidation. Furthermore, the processis not specific in that any of the cellulose ester hydroxyls can beoxidized.

Oxidation of carbohydrates and polysaccharides is a very importantprocess in the chemical industry and a number of useful catalysts forthis transformation have been developed. Some of the most usefulcatalysts belong to the class of compounds referred to as nitroxyl ornitroxide radicals. Typically, these compounds are secondary aminenitroxides with the general structure shown below.

Of the secondary amine N-oxides, the cyclic hindered nitroxyls belongingto the piperidine series have proven to be the most interesting. Thereare many routes for the synthesis of cyclic nitroxyl derivatives in thepiperidine series. The vast majority of the methods use4-oxo-2,2,6,6-tetramethylpiperidine (triacetoneamine) as the commonstarting material, which is generally prepared by the cyclocondensationof acetone and ammonia (Sosnovsky, G.; Konieczny, M., Synthesis, 1976,735-736). Triacetoneamine serves as a common intermediate for thesynthesis of a number of different derivatives such as those shown inScheme 1 below. Of the derivatives shown in Scheme1,2,2,6,6-tetramethylpiperidine-N-oxyl (5, TEMPO) has proven to be thecyclic nitroxyl used in most studies involving oxidation of alcohols.

Oxidation of alcohols with TEMPO under acidic conditions convertsprimary and secondary alcohols to aldehydes and ketones, respectively(Bobbit, J. M.; Ma, Z., J. Org. Chem. 1991, 56, 6110-6114). Generally,over oxidation is not observed, but two molar equivalents of TEMPO permole of substrate are required for the oxidation of the alcohol. Thatis, the reaction is not catalytic.

The use of stoichiometric amounts of TEMPO or its analogues foroxidation of alcohols can be expensive and create difficulties inisolation of the product. As a result, work in this area has focused oncatalytic processes that regenerate the nitrosonium ion in situ by theuse of primary and/or terminal oxidants. The primary oxidant oxidizesthe hydroxy amine back to the nitrosonium ion, and the terminal oxidantserves to regenerate the primary oxidant. In some cases, the primaryoxidant functions as both the primary and terminal oxidant.

It is possible to oxidize alcohols under acidic conditions usingcatalytic amounts of TEMPO or its analogues. However, the solvents forthis process are limited and acid sensitive substrates typically aredestroyed under these conditions. Furthermore, primary and secondaryalcohols are typically converted to aldehydes and ketones, respectively,rather than to a carboxylic acid.

TEMPO catalyzed oxidations of primary alcohols in nonaqueous reactionmedia under acidic conditions (pH<4) can give almost exclusively thecorresponding aldehyde. In aqueous media, some subsequent conversion ofthe aldehyde to a carboxylate is observed, but the aldehyde tocarboxylic acid ratio remains high. As a result, oxidation of primaryalcohols of polysaccharides and carbohydrates under acidic conditionsusing prior art TEMPO catalyzed conditions is of limited utility due tothe fact that the extent of oxidation is limited and the reaction mediais not suitable for many substrates.

As a result, research concerning the oxidation of primary alcohols ofpolysaccharides and carbohydrates with TEMPO and TEMPO analogues hasfocused on oxidation under alkaline conditions. Because mostpolysaccharides and carbohydrates have limited solubility in organicsolvents, most investigations have focused on the use of an aqueousreaction media.

Typical pH and temperature for TEMPO catalyzed oxidation ofpolysaccharides, such as starch, are in the range of 8.5-11.5 at atemperature of −10 to 25° C. (Tetrahedron Letters 1999, 40, 1201-1202;Macromolecules 1996, 29, 6541-6547; Tetrahedron 1995, 51, 8023-32;Carbohydr. Polym. 2000, 42, 51-57; Carbohydr. Res. 2000, 327, 455-461;Carbohydr. Res. 1995, 269, 89-98; WO 96/38484; Recl. Tray. Chim.Pays-Bas 1994, 113, 165-6; Carbohydr. Res. 2001, 330, 21-29; Carbohydr.Lett. 1998, 3, 31-38; EP 1077221 A1; Synthesis 1999, 5, 864-872; J. Mol.Catal. A: Chem. 1999, 150, 31-36). In most cases, the primary oxidant isNaBr and the terminal oxidant is NaOCl.

Oxidation of polysaccharides and carbohydrates under alkaline conditionsusing analogues of TEMPO and other primary oxidants has also beeninvestigated (Carbohydrate Research 2000, 328, 355-363; J. Mol. Catal.A: Chem. 2001, 170, 35-42; J. Catal. 2000, 194, 343-351; Proc.Electrochem. Soc. 1993, 260-7; Carbohydr. Res. 1995, 268, 85-92; EP0979826 A1; U.S. Pat. No. 5,831,043; US 2001/0034442 A1).

It is difficult, if not impossible, to oxidize cellulose esters usingTEMPO under alkaline conditions. One problem is that nearly allcellulose esters are insoluble in water. Additionally, the pH andtemperatures commonly employed can lead to rapid and undesirablecleavage of the acyl substitutents. Furthermore, the polymer backbone israpidly cleaved under these reaction conditions.

Most of the studies involving TEMPO catalyzed oxidation ofpolysaccharides have involved water-soluble polysaccharides orpolysaccharides that are sufficiently reactive so that they can betreated as a suspension in H₂O. Attempts to extend TEMPO mediatedoxidations to cellulose have met with limited success. Cellulose can beoxidized to a water-soluble polyuronic acid after mercerization in NaOHor after regeneration of the cellulose (Cellulose 2002, 9, 75-81;Cellulose 1998, 5, 153-164).

In view of the previous discussion, it would be useful to have routes toaccess carboxylated cellulose ester derivatives with high acid numberswherein the carboxyl group is attached directly to the cellulosebackbone by a carbon-carbon bond. Preferably, such a route would beversatile allowing access to carboxylated cellulose esters having a widerange of acid numbers. It would also be desirable that the carboxylatesbe randomly distributed within the cellulose ester polymer. Throughfunctionalization of the intermediate aldehyde, the correspondingcationic or zwitterionic cellulose ester derivatives could also beaccessed.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides cellulose esterinterpolymers wherein the C2 and C3 positions of each of theanhydroglucose units of the cellulose ester interpolymer are in thealcohol oxidation state, and comprising anhydroglucose units

wherein R₁, R₂, R₃, R₄, and R₅ are independently selected from the groupconsisting of hydrogen and C₂-C₁₂ acyl groups, wherein at least one ofR₁, R₂, R₃, R₄, and R₅ is a C₂-C₁₂ acyl group; and, X is formyl,hydroxymethylene, aminomethyl, R₆—NH—CH₂— or carboxy or a mixturethereof, wherein R₆ is selected from the group consisting of alkyl,aryl, or alkylene-aryl, provided when at least some of X is carboxy, theacid number is greater than 10; wherein the anhydroglucose units A and Bcomprise greater than 65% of the total anhydroglucose units of thecellulose portion of the cellulose ester interpolymer.

In another aspect, the present invention provides cellulose esterinterpolymers comprising a plurality of anhydroglucose units having a C6carboxy group and wherein the cellulose ester interpolymer has anapparent degree of substitution per anhydroglucose unit of C₂-C₁₂ acylof at least about 0.6 and an acid number of greater than 10.

In another aspect, the present invention provides oxidized celluloseinterpolymers having a degree of polymerization of at least 10, an acidnumber of greater than 10, and a random distribution throughout thecellulose interpolymer of anhydroglucose units having a C6 carboxygroup.

In another aspect, the present invention provides cellulose esterinterpolymers comprising anhydroglucose units

wherein R₁, R₂, R₃, R₄, and R₅ are independently selected from the groupconsisting of C₂-C₁₂ acyl groups; X is hydroxymethyl; and wherein theanhydroglucose units A and B comprise greater than 65% of the totalanhydroglucose units of the cellulose portion of the cellulose esterinterpolymer, and the degree of substitution per anhydroglucose unit ofC₂-C₁₂ acyl groups is from about 1.5 to about 2.5.

In another aspect, the present invention provides cellulose esterinterpolymers having a degree of substitution per anhydroglucose unit offormate of 0.5 to 1.3, and a degree of substitution of C₂-C₁₂ acyl of1.5 to 2.5.

In another aspect, the present invention provides a method forconverting a C6 hydroxyl of an anhydroglucose unit of cellulose polymerto a formyl group or a carboxyl group comprising: adding an aminosubstituted cyclic nitroxyl derivative, a primary oxidant, and aterminal oxidant to a cellulose mixture having a pH of less than 4 toform a reaction mixture, wherein the cellulose mixture comprises aC₂-C₁₂ alkyl acid, water, and a cellulose polymer comprisinganhydroglucose units having C6 hydroxyl groups; and passing of areaction period sufficient to effect conversion of a C6 hydroxyl to aformyl group or a carboxy group and thus produce an oxidized celluloseinterpolymer. In a further embodiment, there is provided the aboveprocess, further comprising reacting the oxidized cellulose interpolymerwith a C₂-C₁₂ acyl anhydride or a mixture thereof.

In another aspect, the present invention provides a method forconverting a C6 hydroxyl of an anhydroglucose unit of a cellulose esterinterpolymer to a formyl group or a carboxyl group comprising: adding anamino substituted cyclic nitroxyl derivative, a primary oxidant, and aterminal oxidant to a cellulose mixture having a pH of less than 4 toform a reaction mixture, wherein the cellulose mixture comprises aC₂-C₁₂ alkyl acid, water, and a cellulose ester interpolymer comprisinganhydroglucose units having C6 hydroxyl groups; and passing of areaction period sufficient to effect conversion of a C6 hydroxyl to aformyl group or a carboxy group and thus produce an oxidized celluloseester interpolymer.

In a further aspect of the present invention, there is provided a methodfor preparing a stable form of a cellulose formate ester interpolymercomprising: (1) mixing formic acid, water, and an C₂-C₁₂ acyl anhydrideto form a mixed anhydride mixture at a first contact temperature; (2)contacting the mixed anhydride mixture and a cellulose compound to forma reaction mixture at a second contact temperature; (3) adding an acidcatalyst to the reaction mixture; (4) passing of a formylation period;wherein a resulting cellulose formate ester interpolymer has a degree ofsubstitution per anhydroglucose unit of formate of about 0.5 to about1.5.

In a further aspect of the invention, there is provided a method forpreparing a stable form of a cellulose ester interpolymer comprising:(1) mixing formic acid, water, and an C₂-C₁₂ acyl anhydride to form amixed anhydride mixture at a first contact temperature; (2) contactingthe mixed anhydride mixture and a cellulose compound to form a reactionmixture at a second contact temperature; (3) adding an acid catalyst tothe reaction mixture; (4) passing of a formylation period; (5) adding aC₂-C₁₂ acyl anhydride to the reaction mixture; (6) heating the reactionmixture to a third contact temperature; (7) passing of an acylationperiod; wherein a resulting cellulose ester interpolymer has a degree ofsubstitution per anhydroglucose unit of C₂-C₁₂ acyl of about 1.5 toabout 2.5, and a degree of substitution per anhydroglucose unit offormate of about 0.5 to about 1.5.

In another aspect, the present invention provides a method forconverting a primary alcohol to a formyl, carboxylate, or mixturethereof, comprising: adding a 4-substituted piperidine nitroxylderivative wherein the substitutent is capable of hydrogen bonding, aprimary oxidant, and a terminal oxidant to a mixture to form a reactionmixture, wherein the mixture has a pH of less than about 4 and comprisesa compound comprising a primary alcohol functional group; passing of areaction period sufficient to effect conversion of the primary alcoholfunctional group. In another embodiment, the primary oxidant is a Mn(III) salt.

In another aspect, the present invention provides a coating compositioncomprising anionic, cationic, or zwitterionic C₂-C₁₂ cellulose esterinterpolymers; resins; organic solvents; and, optionally, pigments.

In another aspect, the present invention provides a waterborne coatingcomposition comprising anionic, cationic, or zwitterionic C₂-C₁₂cellulose ester interpolymers; resins; organic solvents; water; base;and, optionally, pigments.

In another aspect, the present invention provides a drug deliverycomposition comprising anionic, cationic, or zwitterionic C₂-C₁₂cellulose ester interpolymers and a therapeutically active agent.

In another aspect, the present invention provides a therapeuticcomposition comprising anionic, cationic, or zwitterionic C₂-C₁₂cellulose ester interpolymers wherein the oxidized cellulose ester is aneffective agent in decreasing or preventing the frequency oftransmission of the human immunodeficiency virus, herpes viruses, orsexually transmitted bacterial infections.

In another aspect, the present invention provides a thermoplasticcomposition comprising anionic, cationic, or zwitterionic C₂-C₁₂cellulose ester interpolymers thermoplastic compatibilizers; one or morecellulose esters; a polymer; and, optionally, natural fibers.

In another aspect, the present invention provides a composite comprisinganionic, cationic, or zwitterionic C₂-C₁₂ cellulose ester interpolymersthermoplastic compatibilizers; one or more neutral cellulose esters; andnatural fibers.

In another aspect, the present invention provides a personal carecomposition comprising anionic, cationic, or zwitterionic C₂-C₁₂cellulose ester interpolymers; resins; solvents; additives; and,optionally, pigments.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a scheme showing various synthetic routes.

FIG. 2 is a graph showing the degree of substitution of formate peranhydroglucose unit as a function of time during a hydrolysis reaction.

FIG. 3 is a collection of ¹³C NMR spectra of C6 carbon resonances forExamples 20-23.

FIG. 4 is a collection of ¹H NMR spectra of cellulose esterinterpolymers described in Examples 1-4.

FIG. 5 is a plot of dissolution versus time (minutes) for aspirin incompressed tablets with oxidized cellulose acetate at pH 1.2 and 6.8 at37° C.

FIG. 6 shows the dissolution of aspirin from coated capsules at 37° C.at pH 1.2 and pH 6.8.

FIG. 7 shows the dissolution of poorly water-soluble drugs from oxidizedcellulose acetate: drug mixtures.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that this invention is not limited to thespecific methods, formulations, and conditions described, as such may,of course, vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular aspects only and isnot intended to be limiting.

In this specification and in the claims that follow, reference will bemade to a number of terms, which shall be defined to have the followingmeanings.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise.

Ranges may be expressed herein as from “about” one particular valueand/or to “about” or another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect.

Throughout this application, where patents are referenced, thedisclosures of these patents in their entireties are hereby incorporatedby reference into this application in order to more fully describe thestate of the art to which this invention pertains.

As illustrated by FIG. 1, starting with native cellulose (I), one objectof the invention is to form a fully substituted cellulose ester or mixedester. Through selection of appropriate substitutents or reactionconditions, one can remove part or all of the acyl substitutent attachedto the C6 primary hydroxyl. Following removal of the C6 substitutent,through the use of suitable catalysts and oxidants one can oxidize thecellulose ester in a mixture of carboxylic acid and water whilemaintaining the DS and molecular weight. The aldehyde (III) shown inFIG. 1 is a critical intermediate. By selection of suitable reactionconditions, the aldehyde may be oxidized to the carboxylate (IV) shownin FIG. 1. Further, we have found that it was possible to modify thereaction conditions such that the intermediate aldehyde could beintercepted with amines allowing the introduction of cationicfunctionality. This then leads to the cationic (V) or zwitterionic (VI)cellulose esters illustrated in FIG. 1. Although isolation ofintermediates during this multi-step reaction is possible and in someinstances desirable, in one embodiment, it is particularly desirable toconvert the cellulose esters to oxidized cellulose esters withoutisolation of any intermediate derivatives.

We also desired to develop an alternative process by which cellulosecould be activated and oxidized before esterifying to form an oxidizedcellulose ester. Key to such a process would be activation of thecellulose in an acidic environment so that the cellulose chains weremore evenly accessible. This would allow the oxidation to proceed insuch a manner that a cellulose ester would ultimately be obtained with ahigh acid number and a relatively homogeneous distribution of oxidizedC6 hydroxyls.

The cellulose triesters to be hydrolyzed and oxidized in the presentinvention can have three substitutents selected independently fromalkanoyls having from 2 to 10 carbon atoms. Examples of cellulosetriesters include cellulose triacetate, cellulose tripropionate, andcellulose tributyrate or mixed triesters of cellulose such as celluloseacetate propionate, and cellulose acetate butyrate. These celluloseesters can be prepared by a number of methods known to those skilled inthe art. For example, cellulose esters can be prepared by heterogeneousacylation of cellulose in a mixture of carboxylic acid and anhydride inthe presence of a catalyst such as H₂SO₄. Cellulose triesters can alsobe prepared by the homogeneous acylation of cellulose dissolved in anappropriate solvent such as LiCl/DMAc or LiCl/NMP.

Those skilled in the art will understand that the commercial term ofcellulose triesters also encompasses cellulose esters that are notcompletely substituted with acyl groups. For example, cellulosetriacetate commercially available from Eastman Chemical Company, Inc.,Kingsport, Tenn., U.S.A., typically has a DS from about 2.85 to about2.95. Hence, cellulose triesters useful for the present invention meansa cellulose ester having DS of at least 2.85.

After esterification of the cellulose to the triester, part of the acylsubstitutents are removed by hydrolysis or by alcoholysis to give asecondary cellulose ester. As noted previously, depending on theparticular method employed, the distribution of the acyl substituentscan be random or non-random. Secondary cellulose esters can also beprepared directly with no hydrolysis by using a limiting amount ofacylating reagent. This process is particularly useful when the reactionis conducted in a solvent that will dissolve cellulose. All of thesemethods yield cellulose esters that are useful for preparing oxidizedcellulose esters.

In one embodiment, the secondary cellulose esters useful in the presentinvention have a weight average molecular weight (Mw) from about 5,000to about 400,000 as measured by GPC. In a further embodiment, the Mw isfrom about 10,000 to about 300,000. In yet a further embodiment, the Mwis from about 25,000 to about 250,000. In one embodiment, the DS of thecellulose esters useful herein is from about 0.5 to about 2.8. In afurther embodiment, the DS is from about 1.7 to about 2.7.

The most common commercial secondary cellulose esters are prepared byinitial acid catalyzed heterogeneous acylation of cellulose to form thecellulose triester. After a homogeneous solution in the correspondingcarboxylic acid of the cellulose triester is obtained, the cellulosetriester is then subjected to hydrolysis until the desired degree ofsubstitution is obtained. After isolation, a randomly secondarycellulose ester is obtained. That is, the relative degree ofsubstitution (RDS) at each hydroxyl is roughly equal.

As illustrated in FIG. 1, the degree by which a cellulose ester can beoxidized is determined by the amount of C6 hydroxyl that is availablefor oxidation. In this sense, a randomly substituted cellulose esterlimits the level of oxidation that can be achieved. Hence, it would beadvantageous to have a method that would provide cellulose esters with ahigh content of C6 hydroxyl.

In this context, we have surprisingly found that regioselectivesubstituted cellulose esters can be easily and rapidly prepared by firsttreating the cellulose with formic anhydride or the mixed formicanhydride prepared in situ from formic acid and acyl anhydride. A secondanhydride or mixture of anhydrides is added and the reaction iscontinued until a triester with the desired molecular weight is formed.Surprisingly, the formate ester is stable and can be isolated andcharacterized at this stage. Typically, we find at this stage that thetriester is principally composed of two monomers: the6-O-formate-2,3-O-acyl substituted monomer and the 2,3,6-O-acylsubstituted monomer. More preferably, the cellulose formate ester is notisolated but is treated with water or an alcohol in such a manner toselectively remove the formate substitutent without affecting the otheracyl substitutents. After isolation, a regioselective substitutedcellulose ester is obtained with a higher level of C6 hydroxyl relativeto the known methods. Typically, we find at this stage that thecellulose ester is principally composed of two monomers: the 2,3-O-acylsubstituted monomer and the 2,3,6-O-acyl substituted monomer. It ispreferred that the ratio of 2,3-O-acyl substituted monomer to the2,3,6-O-acyl substituted monomer be at least 0.67, i.e., at least about40% of the 2,3-O-acyl substituted monomer.

The cellulose that can be used in the regioselective reaction can comefrom a number of sources. Examples of useful cellulose include cellulosefrom wood pulp, bacterial cellulose, or cellulose from annual plantssuch as cotton or corn. In the present invention, it is not necessary totreat the cellulose with water or another agent to activate, i.e.disrupt the hydrogen bonding of the cellulose, prior to esterification.However, in select cases, those skilled in the art will recognize it maybe preferential to activate the cellulose prior to esterification.

The formic acid that can be used to make the formic anhydride or themixed formic anhydride is commercially available and typically contains1-15% H₂O. Formic acid and formic anhydride are inherently not stableand the H₂O serves to stabilize the formic acid. In the presentinvention, after cooling the formic acid solution to the first contacttemperature of about −10 to about 15° C., an equal molar or slightexcess amount of acyl anhydride, based on moles of water, is added tothe aqueous formic acid. The preferred acyl anhydride contains 2-12carbon atoms. The preferred acyl anhydrides are acetic anhydride,propionic anhydride, butyric anhydride, isobutyric anhydride, or amixture thereof. The preferred temperature is from about −5 to about 10°C.

The in situ formed anhydride is adjusted to the desired second contacttemperature of about 10 to about 70° C. In another embodiment, thesecond contact temperature is from about 15 to about 25° C. Afterreaching the second contact temperature, cellulose is added to theanhydride solution. Alternatively, the anhydride solution can be addedto cellulose. After contacting the cellulose with the anhydridesolution, the catalyst is added. The catalyst is any acid capable ofpromoting esterification of cellulose. Examples of such catalystsinclude, but are not limited to, H₂SO₄, HBr, HCl, HClO₄, or mixturesthereof. In another embodiment, the catalyst is H₂SO₄. The amount ofcatalyst that is added is from about 0.25 to about 15 wt % based onweight of cellulose. In another embodiment, the amount of catalyst isfrom about 2.5 to about 7.5 wt %.

Following addition of the catalyst, the slurry of cellulose ismaintained at the second contact temperature for the contact time. Inone embodiment, the contact time is from about 10 to about 60 min. Inanother embodiment, the contact time is from about 20 to about 40 min.

When the contact time with the in situ formed anhydride solution iscomplete, a second C₂-C₁₂ anhydride or mixture of C₂-C₁₂ anhydrides isadded. In one embodiment, the anhydrides or mixtures thereof are C₂-C₄anhydrides. In another embodiment, the anhydrides are acetic, propionic,butyric, isobutyric anhydride or mixtures thereof.

After completing the addition of the second anhydride or mixture ofanhydrides, the cellulose containing solution is adjusted to the thirdcontact temperature. In one embodiment, the third contact temperature isfrom about 30 to about 95° C. In another embodiment, the third contacttemperature is from about 40 to about 60° C. The cellulose containingsolution is maintained at the third contact temperature until acellulose triester with the desired molecular weight is obtained. Inanother embodiment, the second contact time is from about 0.1 to about24 h. In another embodiment, the second contact time is from about 2 toabout 8 h. In one embodiment, the weight-average molecular weight isfrom about 5,000 to about 600,000 g/mol. In another embodiment, themolecular weight is from about 25,000 to about 250,000 g/mol. In yet afurther embodiment, the molecular weight is from about 50,000 to about150,000 g/mol.

When the cellulose triester with the desired molecular weight isobtained, the catalyst can be neutralized with an appropriate base andisolated by addition of a nonsolvent. Examples of suitable basesinclude, but are not limited to, NaOH, KOH, MgCO₃, Mg(OAc)₂, CaCO₃,Ca(OAc)₂, Na₂CO₃, K₂CO₃, NaHCO₃, or mixtures thereof. Examples ofnonsolvents include, but are not limited to, H₂O, MeOH, EtOH, n-PrOH,i-PrOH, i-BuOH, or mixtures thereof. Filtration and drying by methodsknown to those skilled in the art provides a cellulose triester.

In the newly formed triester, the formate substitutent is preferablyattached to the C6 hydroxyl of cellulose. In one embodiment, the totalformate DS is from about 0.7 to about 1.3. In a further embodiment, thetotal formate DS is from about 0.9 to about 1.1. In another embodiment,the formate RDS at C6 is at least 0.4. In yet another embodiment, theformate RDS is at least 0.6.

When a regiospecific substituted cellulose ester with a high C6 hydroxylcontent is desired, the formate ester can be selectively removed bycontacting the fully substituted cellulose formate ester with H₂O or analcohol at a preferred contact temperature and time. In one embodiment,the alcohol is methanol. It is preferred, but not necessary, toneutralize the catalyst prior to hydrolysis or alcoholysis. In oneembodiment, the amount of H₂O or alcohol is from about 5 to about 35 wt%. In another embodiment, the amount of H₂O or alcohol is from about 10to about 25 wt %. In one embodiment, the contact temperature is fromabout 25 to about 95° C. In another embodiment, the contact temperatureis from about 40 to about 60° C. In another embodiment, the contact timeis from about 4 to about 36 h. In yet a further embodiment, the contacttime is from about 8 to about 24 h. For certain applications, it may bedesirable to maintain a low level of formate ester in the secondarycellulose ester. The level of formate ester in the secondary ester canbe controlled by selection of the appropriate contact time andtemperature. The secondary regiospecific substituted cellulose ester canbe isolated in the same manner as the cellulose triester. In general,the RDS of the secondary ester will reflect that established at thetriester stage.

The polysaccharide esters that can be oxidized in the present inventionare those that are soluble in a mixture of carboxylic acid and H₂O andwhich have primary hydroxyls available for oxidation. Examples of suchpolysaccharide esters include starch esters and other polysaccharidesesters having α-1,4 glycosidic linkages, pullulan esters and otherpolysaccharides esters having α-1,3 glycosidic linkages, celluloseesters and other polysaccharides esters having β-1,4 glycosidiclinkages, and other β-glucan esters such as those from chitin, chitosan,fructans, glactomannans, glucomannas, xyloglucans, arabinoxylans and thelike. The most preferred polysaccharide esters are C₂-C₁₀ celluloseesters having primary hydroxyls available for oxidation. Thus, in afurther aspect of the invention, there is provided a method forconverting a primary alcohol to a formyl, carboxylate, or mixturethereof, comprising: adding a 4-substituted piperidine nitroxylderivative wherein the substitutent is capable of hydrogen bonding, aprimary oxidant and a terminal oxidant to a mixture to form a reactionmixture, wherein the mixture has a pH of less than about 4 and comprisesa compound comprising a primary alcohol functional group; passing of areaction period sufficient to effect conversion of the primary alcoholfunctional group, wherein the primary alcohol group is found on theabove listing of polysaccharide esters. In another embodiment of thisaspect of the invention, the primary oxidant is a Mn (III) salt,

In one embodiment, the reaction media for oxidation is a mixture ofcarboxylic acid and H₂O. In another embodiment, the carboxylic acids areC₂-C₁₀ aliphatic carboxylic acids or mixtures thereof. In yet anotherembodiment, the carboxylic acids are those, which correspond to the acylgroups attached to the polysaccharide ester. For example, the carboxylicacid in the oxidation of cellulose propionate may be propionic acid andthe carboxylic acid mixture in the oxidation of cellulose acetatepropionate may be a mixture of propionic acid and acetic acid. In oneembodiment, the amount of water in the carboxylic acid is from about 1to about 60 wt % based on total weight of liquids. In anotherembodiment, the amount of water in the carboxylic acid is from about 5to about 30 wt %.

In one embodiment of the present invention, the catalyst or mediator foroxidation of polysaccharide esters are organic nitroxyl compoundslacking α-hydrogen atoms. In one embodiment, the organic nitroxylcompounds are those arising from the piperidine or pyrrolidine series.In a further embodiment, the organic nitroxyl compounds are those thatcan be derived from 4-oxo-2,2,6,6-tetramethylpiperidine. For thepreparation of cationic C₂-C₁₀ oxidized cellulose esters, the mostpreferred organic nitroxyl compound is2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO). The preference for TEMPOin preparing cationic C₂-C₁₀ oxidized cellulose esters arises from thefact that, when used in combination with appropriate primary oxidants,the oxidation provides a high aldehyde to carboxylate ratio. A highconcentration of aldehyde functionality is necessary for subsequentconversion to the cationic functionality (vide infra). For thepreparation of anionic or zwitterionic C₂-C₁₀ oxidized cellulose esters,in one embodiment, the organic nitroxyl compounds are4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl and derivatives thereofas well as 4-amino-2,2,6,6-tetramethylpiperidine-N-oxyl and derivativesthereof. In another embodiment, the most preferred organic nitroxylcompound for the preparation of anionic or zwitterionic C₂-C₁₀ oxidizedcellulose esters is 4-acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl(NHAcTEMPO). In one embodiment, the amount of organic nitroxyl compoundis from about 0.0001 to about 0.1 molar equivalents per mole ofpolysaccharide ester monomer. In another embodiment, the amount oforganic nitroxyl compound is from about 0.0025 to about 0.075 molarequivalents per mole of polysaccharide ester monomer. In yet a furtherembodiment, the amount organic nitroxyl compound is that amount thatwill give the desired degree of oxidation under the selected reactionconditions. As such, a broad range of organic nitroxyl compound iscontemplated.

The preferred primary oxidants are oxidizing agents capable of oxidizinghydroxyamines that arise from the reduction of organic nitroxyls.Examples of primary oxidants include, but are not limited to halidesalts such as KCl, KBr, NaCl, NaBr, NaI and the like, hypohalites suchas NaOCl, NaOBr and the like, metals such as Fe(III), Mn (II), Mn(III),Cu(II) and the like, and mixtures thereof. For the preparation ofanionic or zwitterionic C₂-C₁₀ oxidized cellulose esters, in oneembodiment, the primary oxidants include KMnO₄, Mn(OAc)₃, Mn₂O₃, MnO₂,Mn(NO₃)₂, MgCl₂, Mg(OAc)₂, Cu(NO₃)₂, KCl, KBr, NaBr, NaCl, and NaOCl.For the preparation of cationic C₂-C₁₀ oxidized cellulose esters, in oneembodiment, the primary oxidants include Mn(NO₃)₂, Cu(NO₃)₂, or mixturethereof. For the preparation of cationic C₂-C₁₀ oxidized celluloseesters using TEMPO, in one embodiment, the primary oxidant is a 1/1mixture of Mn(NO₃)₂ and Cu(NO₃)₂. In another embodiment, the amount ofprimary oxidant is from about 0.0001 to about 0.1 molar equivalents permole of polysaccharide ester monomer. In yet a further embodiment, theprimary oxidant is from about 0.001 to about 0.075 molar equivalents permole of polysaccharide ester monomer. In general, the amount of primaryoxidant is that amount that will give the desired degree of oxidationunder the selected reaction conditions. As such, a broad range ofprimary oxidant is contemplated.

In one embodiment, the terminal oxidants are any oxidizing agentscapable of directly oxidizing hydroxyamines that arise from thereduction of organic nitroxyls or reoxidizing primary oxidants that inturn oxidize the hydroxyamines that arise from the reduction of organicnitroxyls. Examples of terminal oxidants include, but are not limitedto, oxygen, ozone, hypohalites such as NaOCl and the like, peroxidessuch as hydrogen peroxide and the like, peracids such as peracetic acidand the like, and mixtures thereof. In one embodiment, the terminaloxidants include oxygen, NaOCl, peracetic acid, and hydrogen peroxide inaqueous carboxylic acid. In one embodiment, the amount of terminaloxidant is from about 0.1 to about 10 molar equivalents per mole ofpolysaccharide ester monomer. In a further embodiment, the amount ofprimary oxidant is from about 2 to about 5 molar equivalents per mole ofpolysaccharide ester monomer. In yet a further embodiment, the amount ofterminal oxidant is that amount that will give the desired degree ofoxidation under the selected reaction conditions. As such, a broad rangeof terminal oxidant is contemplated.

For the oxidation of cellulose esters and other polysaccharide esters, abroad contact temperature, time, and pH is contemplated. The precisevalues will depend upon the amount of catalyst and oxidant added, thedegree of oxidation needed, and other properties, such as molecularweight, that are desired. In one embodiment, the contact temperature inthe oxidation is from about 25 to about 80° C. In another embodiment,the contact temperature is from about 50 to about 60° C. In anotherembodiment, the contact time is from about 0.1 to about 36 h. In afurther embodiment, the contact time is from about 3 to about 12 h. Inyet a further embodiment, the contact time is equal to or slightlygreater (about 0.01 to about 1 h) than the time that is required to addthe terminal oxidant. In one embodiment, the addition time of terminaloxidant is from about 0.1 to about 35 h. In another embodiment, theterminal oxidant addition time is from about 2 to about 11 h. In oneembodiment, the contact pH can range from about 0.1 to about 4. Theprecise value will be determined by the pH of the carboxylic acid and ifthe acid used in the esterification or hydrolysis of the polysaccharideester was neutralized prior to the oxidation. In another embodiment, thecontact pH is less than about 2.0. Although it is possible to controlpH, it should be understood that in this invention, it is preferred thatthe pH not be controlled to a particular value during the reaction butthat the pH should be allowed to drift during the reaction.

Oxidized cellulose esters can be isolated by a number of techniques suchas precipitation in a nonsolvent, by spray drying, by spinning offibers, etc. In one embodiment, the method is by precipitation intononsolvents such as H₂O, H₂O/C₂-C₄ carboxylic acid mixtures, C₁-C₄alcohols, C₁-C₄ esters of acetate or propionate, and the like. Thesolvent used depends upon the degree of oxidation, the molecular weightof the oxidized polysaccharide, and the number of carbons in the acylsubstitutents. For oxidized cellulose esters such as oxidized celluloseacetate, the preferred nonsolvents are C₂-C₄ alcohols such as isopropylalcohol or n-butanol. In the case of oxidized cellulose esters such asoxidized cellulose butyrates, the preferred nonsolvent is H₂O containingfrom about 5 wt % to about 25 wt % of a C₁ to C₄ carboxylic acid.

In the case of oxidized cellulose esters, the amount of oxidation ismost conveniently measured by determining the acid number. Acid numberis defined as the mg of base (KOH) required to neutralize 1 g ofoxidized cellulose ester. For cellulose esters, the acid number of theoxidized cellulose ester will be set by the intended end use applicationand hence a very broad acid number is anticipated. In one embodiment,the acid number is greater than 10. In another embodiment, the acidnumber is greater than 30. In another embodiment, the acid number isgreater than 30 and less than 150. In another embodiment, the acidnumber is greater than 30 and less than 130. In another embodiment, theacid number is greater than 30 and less than 90.

Those skilled in the art will recognize that a number of techniques canbe used to determine the acyl DS of polysaccharide esters. In the caseof oxidized cellulose esters, the acyl DS value will also depend uponthe technique that is used to measure the DS. Proton NMR is a common andpreferred technique for measuring the acyl DS of cellulose esters. Thismethod relies on determining the amount of glucose monomer byintegration of the backbone region of the cellulose ester, which is thendivided by 7, which is the number of protons normally attached to theglucose monomer. However, oxidation of the glucose monomer will reducethe number of protons depending upon the extent of oxidation. Hence, ifno hydrolysis of acyl substitutents occurs during the oxidation, thenormal NMR method will give an acyl DS that will increase linearly withoxidation. If hydrolysis of the acyl substitutents is occurring, theincrease in DS will not be linear. Thus, proton NMR can provide anindication of oxidation for a particular sample. The acyl DS that isobtained by proton NMR for the oxidized cellulose ester is referred toas the apparent acyl DS.

The apparent acyl DS of the oxidized cellulose esters is a crucialproperty for virtually all applications and the preferred apparent acylDS will vary depending upon the intended application. In one embodimentof this invention, the apparent acyl DS will be at least 0.6. In afurther embodiment, the apparent acyl DS is from about 1.5 to about 3.1.In a further embodiment, the apparent acyl DS is from about 1.7 to about2.8.

The molecular weight of the oxidized cellulose esters is anotherimportant property for most applications and the preferred molecularweight will vary depending upon the intended application. In the case ofmolecular weight, by selection of the acyl group attached to thecellulose polymer and by control of the amount of aldehyde and hydroxylfunctional groups in the final product through selection of appropriatereaction conditions, it is possible to have molecular weights in theoxidized cellulose ester that are less than or greater than that of thecellulose ester used in the oxidation. The increase in molecular weightabove that of the starting molecular weight of the cellulose esters isthought to be due to small concentrations of aldehyde functional groupsthat lead to effective cross-linking of the oxidized cellulose ester byformation of acetal or hemiacetal linkages. In the case of the apparentmolecular weight of the oxidized cellulose ester, in one embodiment theweight-average molecular weight is at least 5,000 g/mol. In anotherembodiment, the range for molecular weight is from about 10,000 to about900,000 g/mol. In a further embodiment, the range is from about 20,000to about 400,000 g/mol.

As noted, the ratio of carboxylate to aldehyde can be used to adjust themeasured molecular weight of the oxidized cellulose ester. This ratiocan also be used to gain entry into a number of unique oxidizedcellulose ester derivatives. The ratio of carboxylate to aldehyde can beadjusted through selection of appropriate reaction conditions. Thereaction parameters, which can impact this ratio, include waterconcentration in the reaction media, type and concentration of organicnitroxyl compound, type and concentration of primary and terminaloxidant, reaction temperature and time, and the type of cellulose esterbeing oxidized. Those skilled in the art will understand that there arecomplex interactions among these parameters and that there are many waysto obtain the same carboxylate to aldehyde ratio by varying theseparameters. The disclosure of this invention is sufficient to teach oneof ordinary skill in the art how to arrive at a particular carboxylateto aldehyde ratio.

For anionic C₂-C₁₀ oxidized cellulose esters, in one embodiment, theratio of carboxylate to aldehyde will be at least 5:1. In anotherembodiment, the carboxylate to aldehyde range is from about 6:1 to about100:1. In another embodiment, the range is when the carboxylate toaldehyde range is from about 10:1 to about 50:1. In some cases, it maybe desirable that that there be no aldehyde.

As a precursor for cationic C₂-C₁₀ oxidized cellulose esters, in oneembodiment, the ratio of carboxylate to aldehyde will be less than 1:5.In some cases, it is preferred that there be no carboxylate. In oneembodiment, the carboxylate to aldehyde range is from about 1:6 to about1:100. In another embodiment, the carboxylate to free aldehyde range isfrom about 1:10 to about 1:50.

In one embodiment, the cellulose ester interpolymer has a degree ofpolymerization of at least 10. In another embodiment, the celluloseester interpolymer has a degree of polymerization of at least 25. In afurther embodiment, the cellulose ester interpolymer has a degree ofpolymerization of between 25 and 50. In yet another embodiment, thecellulose ester interpolymer has a degree of polymerization of at least250.

As a precursor for zwitterionic C₂-C₁₀ oxidized cellulose esters, it ispreferred that the ratio of carboxylate to aldehyde be from about 5:1 toabout 1:5. A more preferred range is when the carboxylate to aldehyderange is from about 4:1 to about 1:4. An even more preferred range isfrom about 2:1 to about 1:2.

In preparing cationic or zwitterionic C₂-C₁₀ oxidized cellulose esters,the aldehyde functionality is converted to cationic functionality. Theconversion of the aldehyde functionality can occur during the oxidationor immediately after oxidation but before isolation of the oxidizedproduct. Alternatively, the cationic or zwitterionic oxidized celluloseester precursor can be isolated and converted to the cationic orzwitterionic oxidized cellulose ester in post reactions. In the case ofisolation of the oxidized cellulose ester prior to conversion to thecationic or zwitterionic oxidized cellulose ester, it is preferred thatthe oxidized cellulose ester not be dried prior to the reductiveamination step. For example, the oxidized cellulose ester may beprecipitated in a non-solvent such as methanol. The oxidized celluloseis then stored methanol wet until ready for use. The methanol can beremoved by dissolving the oxidized cellulose ester in the reactionreagents, e.g. acetic acid and benzyl amine, and bubbling air or N₂through the solution to remove the methanol. Because fewer acetallinkages are formed relative to drying the oxidized cellulose ester,this process allows the oxidized cellulose to be more easily dissolvedin the reaction solvents.

The aldehyde functionality can be converted to a cationic functionalityby treating the aldehyde with a source of NH₃ or a primary amine in thepresence of hydrogen and a hydrogenation catalyst (reductive amination).In one embodiment, the source of NH₃ is ammonia gas or other sourcessuch as NH₃Cl. The preferred amines are primary amines having from 1 to14 carbon atoms. Examples of amines include, but are not limited to,ethylamine, propylamine, butylamine, benzylamine, or mixture thereof. Inone embodiment, the hydrogenation catalyst is Pd supported on inertsubstances such as carbon. Other reducing agents can also be utilizedsuch as sodium cyanoborohydride, sodium borohydride, or amine salts offormic acid.

The amount of amine present in the cationic or zwitterionic oxidizedcellulose ester can be determined by a variety of methods such as bytitration methods similar to that used to determine acid number or byother methods such as proton NMR. For the purpose of this invention, thequantity of amine in the cationic or zwitterionic oxidized celluloseester is preferably determined by proton NMR when possible. In thisregard, the DS of amine is referred to as the apparent amine DS for thesame reasons described above. In one embodiment of the presentinvention, the apparent amine DS is at least about 0.05. In anotherembodiment, the apparent amine DS is about 0.2 to about 0.7.

In certain instances, it may be preferred to first oxidize apolysaccharide then esterify the oxidized polysaccharide. Hence, anotheraspect of the present invention is oxidation of polysaccharides withavailable primary hydroxyls in a mixture of carboxylic acid and H₂O.Examples of such preferred polysaccharides include starch and otherpolysaccharides having α-1,4 glycosidic linkages, pullulan and otherpolysaccharides having α-1,3 glycosidic linkages, cellulose and otherpolysaccharides having β-1,4 glycosidic linkages, and other β-glucanssuch as those from chitin, chitosan, fructans, glactomannans,glucomannas, xyloglucans, arabinoxylans and the like. The most preferredpolysaccharide is cellulose. The limitations noted above forpolysaccharide esters are also applicable to the oxidation ofpolysaccharides. In one embodiment, in the present invention foroxidation of polysaccharides, it is preferred that the pH during theoxidation be less than about 4 and, in another embodiment, less thanabout 2. In contrast to oxidation of cellulose in a basic media, noprior treatment of the cellulose is necessary as the reaction media foroxidation of cellulose by the methods of the present invention issufficient to disrupt the crystallinity of the native cellulose. In oneembodiment, the cellulose oxidized by the methods of the presentinvention has an acid number of at least 10. In another embodiment, theoxidized cellulose has an acid number of at least 30. It is alsopreferred that the oxidized cellulose prepared by the methods of thepresent invention have little solubility in water. That is, due to moreeven accessibility of the primary hydroxyls and resulting evendistribution of carboxylates, the product is characterized by havingonly a small or no water-soluble fractions. The methods of the presentinvention are compatible with the methods commonly utilized in theesterification of cellulose. That is, after filtering to remove theliquids, the oxidized cellulose can be esterified by methods well knownto those skilled in the art.

The cellulose ester interpolymers of the present invention and othercompositions disclosed herein may be useful in a number of differenttypes of applications, for example, the cellulose ester interpolymerswherein the C2 and C3 positions of each of the anhydroglucose units ofthe cellulose ester interpolyer are in the alcohol oxidation state, andcomprising anhydroglucose units

wherein R₁, R₂, R₃, R₄, and R₅ are independently selected from the groupconsisting of hydrogen and C₂-C₁₂ acyl groups, wherein at least one ofR₁, R₂, R₃, R₄, and R₅ is a C₂-C₁₂ acyl group; and X is formyl,hydroxymethylene, aminomethyl, R₆—NH—CH₂— or carboxy or a mixturethereof, wherein R₆ is selected from the group consisting of alkyl,aryl, or alkylene-aryl, provided when at least some of X is carboxy, theacid number is greater than 10; wherein the anhydroglucose units A and Bcomprise greater than 65% of the total anhydroglucose units of thecellulose portion of the cellulose ester interpolymer. These celluloseester interpolymers may be useful in a variety of coating compositionssuch as enteric coatings for medicaments, architectural coatings,maintenance coatings, industrial coatings, automotive coatings, textilecoatings, inks, adhesives, and coatings for metal, paper, wood, andplastics, as binder resins. The cellulose ester interpolymers may beparticularly useful in waterborne coating applications containingpigments.

Additionally, the oxidized cellulose esters of the present invention maybe useful in drug delivery compositions, as an antiviral agent, as acompatibilizer in thermoplastic compositions, and in personal carecompositions.

Accordingly, in one aspect, this invention relates to coatingcompositions comprising oxidized cellulose esters of the presentinvention. The oxidized cellulose esters of the invention may beincorporated into coating compositions in the same manner as knowncellulose esters and are used with the conventional components and oradditives of such compositions. The coating compositions may be clear orpigmented. Coating compositions containing carboxylated cellulose etheresters are known in the art and are described, for example, in U.S. Pat.No. 5,668,273, incorporated herein by reference.

In one embodiment, there provided coating compositions utilizing thecellulose ester interpolymers of the invention; in one embodiment, thecellulose ester interpolymers wherein the C2 and C3 positions of each ofthe anhydroglucose units of the cellulose ester interpolyer are in thealcohol oxidation state, and comprising anhydroglucose units

-   -   wherein R₁, R₂, R₃, R₄, and R₅ are independently selected from        the group consisting of hydrogen and C₂-C₁₂ acyl groups, wherein        at least one of R₁, R₂, R₃, R₄, and R₅ is a C₂-C₁₂ acyl group;        and, X is formyl, aminomethyl, R₆—NH—CH₂— or carboxy or a        mixture thereof, wherein R₆ is selected from the group        consisting of alkyl, aryl, or alkylene-aryl, provided when at        least some of X is carboxy, the acid number is greater than 10;        wherein the anhydroglucose units A and B comprise greater than        65% of the total anhydroglucose units of the cellulose portion        of the cellulose ester interpolymer.

Thus, in one embodiment, the invention provides a coating compositioncomprising

-   -   (i) about 0.1 to about 50 weight percent, based on the total        weight percent of (i) and (ii), in said composition, of        cellulose ester interpolymers wherein the C2 and C3 positions of        each of the anhydroglucose units of the cellulose ester        interpolymer are in the alcohol oxidation state, and comprising        anhydroglucose units

-   -   wherein R₁, R₂, R₃, R₄, and R₅ are independently selected from        the group consisting of hydrogen and C₂-C₁₂ acyl groups, wherein        at least one of R₁, R₂, R₃, R₄, and R₅ is a C₂-C₁₂ acyl group;        and, X is formyl, aminomethyl, R₆—NH—CH₂— or carboxy or a        mixture thereof, wherein R₆ is selected from the group        consisting of alkyl, aryl, or alkylene-aryl, provided when at        least some of X is carboxy, the acid number is greater than 10;        wherein the anhydroglucose units A and B comprise greater than        65% of the total anhydroglucose units of the cellulose portion        of the cellulose ester interpolymer; and,    -   (ii) about 50 to 99.9 weight percent, based on the total weight        of (i) and (ii) in said composition, of a resin which is other        than (i); and    -   (iii) at least one organic solvent;    -   wherein the total weight of (i) and (ii) is about 5 to 70 weight        percent of the total weight of (i), (ii), and (iii).

In one embodiment, the cellulose esters interpolymers are anionic C₂-C₈cellulose esters having an acid number from about 10 to about 200. In afurther embodiment, the oxidized cellulose esters are anionic C₂-C₄cellulose esters having an acid number from about 30 to about 80. Incoating compositions, the concentration of oxidized cellulose esters istypically from about 0.1 to about 50 wt % based on total weight ofoxidized cellulose ester and added resin. In another embodiment, theconcentration of oxidized cellulose ester is from about 3 to about 30 wt%.

The cellulose ester interpolymers may be compatible with a wide range ofresinous materials such as those used in coating and ink compositions.Classes of resins with which the carboxylated cellulose esters arecompatible include, but are not limited to, polyesters,polyester-amides, cellulose esters, alkyds, polyurethanes, epoxy resins,polyamides, acrylics, vinyl polymers, polyisocyanates, melamines,silicone resins, and nitrocellulose. Typically, the concentration of thecellulose ester interpolymer in the coating composition is from about0.1 to about 50 wt % based on total weight of oxidized cellulose esterand resin. In another embodiment, the concentration of cellulose esterinterpolymer is from about 5 to about 30 wt %.

The cellulose ester interpolymers of the present invention arecompatible with a number of solvents. These solvents include, but arenot limited to methanol; ethanol; methylene chloride; diacetone alcohol;lower alkanoic acids, such as formic acid, acetic acid, and propionicacid; lower alkyl ketones, such as acetone, methyl ethyl ketone, methylpropyl ketone, methyl isobutyl ketone, and methyl n-amyl ketone; esters,such as methyl acetate, ethyl acetate, isopropyl acetate, n-propylacetate, n-butyl acetate, 2-ethylhexyl acetate, isobutyl acetate,2-butoxy-ethyl acetate, 1-methoxy-2-propyl acetate, 2-ethoxy-ethylacetate, ethyl-3-ethoxypropionate, isobutyl isobutyrate, and2,2,4-trimethyl-1,3-pentanediol monoisobutyrate; ethers such as ethyleneglycol butyl ether, propylene glycol propyl ether, 2-ethoxyethanol,2-propoxyethanol, and 2-butoxyethanol; and mixtures thereof. Theconcentration of solvent in the coating compositions containing thecellulose ester is typically from about 30 to about 95 wt % based on thetotal weight of oxidized cellulose ester, resin, and solvent. Thoseskilled in the art will understand that selection of the compatiblesolvent will depend upon a number of factors including DS of theoxidized cellulose ester, the type of substitutent, the degree ofoxidation, the molecular weight, and the like.

A coating formulation containing the cellulose esters interpolymers ofthe present invention may be applied to a variety of surfaces,substrates, or articles, e.g., paper; plastic; metal such as steel andaluminum; wood; gypsum board; concrete; brick; masonry; or galvanizedsheeting. The type of surface, substrate, or article to be coatedgenerally determines the type of coating formulation used. The coatingformulation may be applied using means known in the art. For example, acoating formulation may be applied by spraying, brushing, rolling or anyother application method to coat a substrate.

The cellulose esters interpolymers of the invention are also useful as amajor film-forming component in both curing and non-curing finishes ofwood coatings. Accordingly, the invention also relates to curing typewood finishes comprising from about 5 to about 20 wt % an oxidizedcellulose ester of the present invention, about 15 to about 25 wt % ofan alkyd resin, about 2 to about 5 percent by weight of a melamineresin, or up to about 5 to about 10 percent by weight of a ureaformaldehyde resin, a relatively small amount of a silicone resin and asolvent system comprising suitable solvents such as xylene, toluene,ethanol, n-butyl alcohol, and methyl ethyl ketone. Flatting agents, suchas SYLOID 83 and SYLOID 378 available from W.R. Grace, may also beemployed.

The cellulose esters interpolymers of the present invention can beformulated into ink formulations. Here, the oxidized cellulose esterfunctions as a medium to disperse the pigments for the ink and alsoserve as a major film-forming resin. Thus, another embodiment of theinvention relates to ink compositions comprising from about 30 to about70% by weight of a oxidized cellulose ester, from about 30 to about 70%by weight of an ink pigment and a solvent present in an amount effectiveto provide a viscosity suitable for applying the ink composition underthe desired conditions.

Ink compositions of the invention may also contain common ink additivesdepending on need of a particular ink or printing method. Such inkadditives include, but are not limited to wetting agents, levelingagents, rheology additives, additives to promote resolubility/rewet onthe press, coalescing aids, pigment wetting agents, dispersing agents,surfactants, waxes, defoaming agents, antifoaming agents, and modifyingpolymers or co-resins. The concentration of the pigment depends upon theparticular pigment employed and the color and degree of hiding desiredin the ink composition. Pigments, which are useful in the inkcompositions of the invention, are those well known in the art and aredescribed, for example, in Kirk-Othmer Encyclopedia of ChemicalTechnology, 2d Ed., Vol. 11, pp. 613-615. The solvents useful in the inkcompositions of the invention are also well known in the art and aredescribed, for example, in Kirk-Othmer Encyclopedia of ChemicalTechnology, 2d Ed., Vol. 11, pp. 621-623. Preferred solvents includeethanol, ethyl acetate, isopropanol, diacetone alcohol, ethylene glycolmonoethyl ether, ethylene glycol monobutyl ether, and mixtures thereof.

Cellulose esters interpolymers of the present invention are particularlyuseful as a pigment dispersing agent. Non-oxidized cellulose esters havefound utility in pigment dispersions by blending the cellulose ester anda pigment with heat and/or shear to disperse the pigment. In thismanner, pigments can be dispersed in coating formulations, therebyproviding high coloring power and good transparency while using aminimal amount of pigment. Such pigment dispersions can be improved bythe use of the oxidized cellulose esters of the present invention inplace of conventional cellulose esters. We have found that the oxidizedcellulose esters of the present invention impart markedly improvedwetting properties to the pigment dispersion. Mixtures of oxidizedcellulose esters and pigments at weight ratios of about 20:80 to 50:50may be prepared. These dispersions can be prepared on a two-roll mill orin a ball mill, Kady mill, sand mill, and the like.

Thus, in one embodiment, the invention provides a pigment dispersioncomprising about 40 to 90 weight percent by weight of at least onepigment and correspondingly about 10 to 60 weight percent of celluloseester interpolymers wherein the C2 and C3 positions of each of theanhydroglucose units of the cellulose ester interpolyer are in thealcohol oxidation state, and comprising anhydroglucose units

-   -   wherein R₁, R₂, R₃, R₄, and R₅ are independently selected from        the group consisting of hydrogen and C₂-C₁₂ acyl groups, wherein        at least one of R₁, R₂, R₃, R₄, and R₅ is a C₂-C₁₂ acyl group;        and X is formyl, aminomethyl, R₆—NH—CH₂— or carboxy or a mixture        thereof, wherein R₆ is selected from the group consisting of        alkyl, aryl, or alkylene-aryl, provided when at least some of X        is carboxy, the acid number greater than 10; wherein the        anhydroglucose units A and B comprise greater than 65% of the        total anhydroglucose units of the cellulose portion of the        cellulose ester interpolymer.

The oxidized cellulose esters and pigment dispersions can be formulatedinto either lacquer or enamel type coatings where they are expected tobe useful as rheology modifiers and/or binder components providingimproved aluminum flake orientation and improved hardness. They can beapplied to a substrate in the form of an organic solvent solution, anamine neutralized waterborne dispersion, a fully neutralizedaqueous/organic colloidal dispersion, or as a zero VOC dispersion inaqueous ammonia. It is further expected that they will provide a waterclear, high gloss, protective coating for a variety of substrates,especially metal and wood.

The cellulose ester interpolymers of the present invention can berelatively hard polymers and have high glass transition temperatures.They can be added to other resins to improve the coating hardness and toimprove properties such as slip, sag resistance, mar resistance, flow,leveling, and dry time. To further improve the toughness, cross linkerssuch as melamines or isocyanates may be added to react with the hydroxylcontaining oxidized cellulose esters or with other resins. The preferredmelamine cross-linking agents include hexamethoxymethylamine,tetramethoxymethylbenzo-guanamine, tetramethoxymethylurea, mixedbutoxy/methoxy substituted melamines, and the like. Typical isocyanatecross linking agents and resin include hexamethylene diisocyanate(HMDI), isophorone diisocyanate (IPDI), and toluene diisocyanate.

Because of the carboxylates present on some of the cellulose esterinterpolymers of the present invention, one could use the usual crosslinkers and resins used with carboxyl functional resins, e.g., epoxyresins or glycidyl-functional resins. Preferred epoxy functional resinsgenerally have a molecular weight of about 300 to about 4000, and haveapproximately 0.05 to about 0.99, epoxy groups per 100 g of resin (i.e.,100-2000 weight per epoxy (WPE)). Such resins are widely known and arecommercially-available under the EPON trademark of the Shell ChemicalCompany, the ARALDITE trademark of CIBA-Geigy, and D.E.R. resins of theDow Chemical Company.

As noted, the cellulose ester interpolymers of the present invention areparticularly useful in waterborne coating compositions. The preferredcellulose ester interpolymers are anionic C₂-C₈ cellulose esters havingan acid number from about 10 to about 200. The most preferred celluloseester interpolymers are anionic C₂-C₄ cellulose esters having an acidnumber from about 30 to about 80.

The cellulose ester interpolymers of this invention may be dissolved inorganic solvents, partially neutralized, and dispersed in water.Examples of such organic solvents include but are not limited to2-butanone, methyl amyl ketone, methanol, ethanol, ethyl3-ethoxypropionate, ethylene glycol monoethyl ether, ethylene glycolmonopropyl ether, and ethylene glycol monobutyl ether and the like.Dispersion of the modified cellulose ester of the present invention inwater requires about 10 to about 100% neutralization of the pendantcarboxylate groups with an amine. Typical amines include but are notlimited to ammonia, piperidine, 4-ethylmorpholine, diethanolamine,triethanolamine, ethanolamine, tributylamine, dibutylamine, anddimethylamino ethanol.

In waterborne coating compositions, the concentration of the resin inthe coating composition is from about 0.1 to about 50 wt % based ontotal weight of oxidized cellulose ester and resin. More preferred iswhen the concentration of resin is from about 5 to about 30 wt %. Theconcentration of cellulose ester interpolymers is typically from about0.1 to about 50 wt % based on total weight of oxidized cellulose esterand added resin. More preferred is when the concentration of oxidizedcellulose ester is from about 0.5 to about 30 wt %. The weight of resinand oxidized cellulose ester in the total composition is from about 5 toabout 70 wt %. More preferred is when the weight of resin and oxidizedcellulose ester in the total composition is from about 10 to about 50 wt%. The organic solvent preferably comprises from about 0 to about 20 wt% of the total composition. More preferred is when the organic solventpreferably comprises from about 5 to about 15 wt % of the totalcomposition.

Thus, in one embodiment, the invention provides a waterborne coatingcomposition comprising

-   -   (i) about 0.1 to about 50 weight percent, based on the total        weight percent of (i) and (ii), in said composition, of        cellulose ester interpolymers wherein the C2 and C3 positions of        each of the anhydroglucose units of the cellulose ester        interpolyer are in the alcohol oxidation state, and comprising        anhydroglucose units

-   -   wherein R₁, R₂, R₃, R₄, and R₅ are independently selected from        the group consisting of hydrogen and C₂-C₁₂ acyl groups, wherein        at least one of R₁, R₂, R₃, R₄, and R₅ is a C₂-C₁₂ acyl group;        and, X is formyl, hydroxymethylene, aminomethyl, R₆—NH—CH₂— or        carboxy or a mixture thereof, wherein R₆ is selected from the        group consisting of alkyl, aryl, or alkylene-aryl, provided when        at least some of X is carboxy, the acid number is greater than        10; wherein the anhydroglucose units A and B comprise greater        than 65% of the total anhydroglucose units of the cellulose        portion of the cellulose ester interpolymer; wherein at least        about 25 percent of all free carboxyl groups on said        interpolymer have been neutralized with a base; and    -   (ii) at least one compatible water-soluble or water dispersible        resin;    -   (iii) water; and    -   (iv) at least one organic solvent;    -   wherein the total weight of (i) and (ii) is between 5 and 50        weight percent of the total composition and the organic solvent        comprises less than 20 weight percent of the total weight of the        composition.

As a further aspect of the present invention, the above compositions arefurther comprised of one or more coatings additives. Such additives aregenerally present in a range of about 0.1 to 15 weight percent, based onthe total weight of the composition. Examples of such coatings additivesinclude leveling, rheology, and flow control agents such as silicones,fluorocarbons or cellulosics; flatting agents; pigment wetting anddispersing agents; surfactants; ultraviolet (UV) absorbers; UV lightstabilizers; tinting pigments; defoaming and antifoaming agents;anti-settling, anti-sag and bodying agents; anti-skinning agents;anti-flooding and anti-floating agents; fungicides and mildewcides;corrosion inhibitors; thickening agents; or coalescing agents.

Specific examples of additional coatings additives can be found in RawMaterials Index, published by the National Paint & Coatings Association,1500 Rhode Island Avenue, N.W., Washington, D.C. 20005.

Examples of flatting agents include synthetic silica, available from theDavison Chemical Division of W. R. Grace & Company under the trademarkSYLOID; polypropylene, available from Hercules Inc., under the trademarkHERCOFLAT; synthetic silicate, available from J.M Huber Corporationunder the trademark ZEOLEX.

Examples of dispersing agents and surfactants include sodiumbis(tridecyl)sulfosuccinnate, di(2-ethyl hexyl)sodium sulfosuccinnate,sodium dihexylsulfosuccinnate, sodium dicyclohexyl sulfosuccinnate,diamyl sodium sulfosuccinnate, sodium diisobutyl sulfosuccinate,disodium iso-decyl sulfosuccinnate, disodium ethoxylated alcohol halfester of sulfosuccinnic acid, disodium alkyl amido polyethoxysulfosuccinnate, tetrasodium N-(1,2-dicarboxy-ethyl)-N-oxtadecylsulfosuccinnamate, disodium N-octasulfosuccinnamate, sulfatedethoxylated nonylphenol, 2-amino-2-methyl-1-propanol, and the like.

Examples of viscosity, suspension, and flow control agents includepolyaminoamide phosphate, high molecular weight carboxylic acid salts ofpolyamine amides, and alkyl amine salt of an unsaturated fatty acid, allavailable from BYK Chemie U.S.A. under the trademark ANTI TERRA. Furtherexamples include polysiloxane copolymers, polyacrylate solution,cellulose esters, hydroxyethyl cellulose, hydrophobically-modifiedhydroxyethyl cellulose, hydroxypropyl cellulose, polyamide wax,polyolefin wax, carboxymethyl cellulose, ammonium polyacrylate, sodiumpolyacrylate, and polyethylene oxide.

Several proprietary antifoaming agents are commercially available, forexample, under the trademark BRUBREAK of Buckman Laboratories Inc.,under the BYK trademark of BYK Chemie, U.S.A., under the FOAMASTER andNOPCO trademarks of Henkel Corp./Coating Chemicals, under the DREWPLUStrademark of the Drew Industrial Division of Ashland Chemical Company,under the TROYSOL and TROYKYD trademarks of Troy Chemical Corporation,and under the SAG trademark of Union Carbide Corporation.

Examples of fungicides, mildewcides, and biocides include4,4-dimethyloxazolidine, 3,4,4-trimethyl-oxazolidine, modified bariummetaborate, potassium N-hydroxy-methyl-N-methyldithiocarbamate,2-(thiocyano-methylthio)benzothiazole, potassium dimethyldithiocarbamate, adamantane, N-(trichloromethylthio)phthalimide,2,4,5,6-tetrachloroisophthalonitrile, orthophenyl phenol,2,4,5-trichlorophenol, dehydroacetic acid, copper naphthenate, copperoctonate, organic arsenic, tributyl tin oxide, zinc naphthenate, andcopper 8-quinolinate.

Examples of U.V. absorbers and U.V. light stabilizers includesubstituted benzophenone, substituted benzotriazole, hindered amine, andhindered benzoate, available from American Cyanamide Company under thetrade name Cyasorb UV, and available from Ciba Geigy under the trademarkTINUVIN, and diethyl-3-acetyl-4-hydroxy-benzyl-phosphonate,4-dodecyloxy-2-hydroxy benzophenone, and resorcinol monobenzoate.

Pigments suitable for use in the coating compositions envisioned by thepresent invention are the typical organic and inorganic pigments,well-known to one of ordinary skill in the art of surface coatings,especially those set forth by the Colour Index, 3d Ed., 2d Rev., 1982,published by the Society of Dyers and Colourists in association with theAmerican Association of Textile Chemists and Colorists. Examplesinclude, but are not limited to the following: CI Pigment White 6(titanium dioxide); CI Pigment Red 101 (red iron oxide); CI PigmentYellow 42, CI Pigment Blue 15, 15:1, 15:2, 15:3, 15:4 (copperphthalocyanines); CI Pigment Red 49:1; and CI Pigment Red 57:1.

This invention also relates to oral drug delivery compositionscomprising the cellulose ester interpolymers of the present invention.In one aspect, the cellulose ester interpolymers are used as an entericcoating for a solid core containing the therapeutic agent. In anotheraspect, the cellulose ester interpolymers are used as a component in ablend used as an enteric coating. In yet another aspect, the celluloseester interpolymers are used as release rate modifiers or solubilitymodifiers of therapeutic agents from a solid core. In still yet anotheraspect, physical mixtures of cellulose ester interpolymers andsolubility modifiers are used for the controlled release of therapeuticagents from a solid core. In a further aspect, vesicles of celluloseester interpolymers containing therapeutic agents acts as release rateand solubility modifiers in the controlled release of therapeutic agentsfrom a solid core. In a still further aspect, the cellulose esterinterpolymers are bioadhesive components in a solid core and act toincrease the bioabsorption of therapeutic agents.

In drug delivery compositions, in one embodiment, the cellulose esterinterpolymers are anionic, cationic, or zwitterionic C₂-C₁₂ celluloseesters. The preferred cellulose ester interpolymers will be determinedby the mode selected for delivery of the therapeutic agent from the oralformulation.

In one embodiment, the invention provides an oral pharmaceuticalcomposition comprising one or more therapeutic agents having coatedthereon or admixed therewith a composition comprising one or morecellulose ester interpolymers wherein the C2 and C3 positions of each ofthe anhydroglucose units of the cellulose ester interpolyer are in thealcohol oxidation state, and comprising anhydroglucose units

whereinR₁, R₂, R₃, R₄, and R₅ are independently selected from the groupconsisting of hydrogen and C₂-C₁₂ acyl groups, wherein at least one ofR₁, R₂, R₃, R₄, and R₅ is a C₂-C₁₂ acyl group; and,X is formyl, hydroxymethylene, aminomethyl, R₆—NH—CH₂— or carboxy or amixture thereof, wherein R₆ is selected from the group consisting ofalkyl, aryl, or alkylene-aryl, provided when at least some of X iscarboxy, the acid number is greater than 10; wherein the anhydroglucoseunits A and B comprise greater than 65% of the total anhydroglucoseunits of the cellulose portion of the cellulose ester interpolymer.

In the case in which the cellulose ester interpolymers are used asenteric coatings of a solid core containing at least one therapeuticagent, in one embodiment, the cellulose ester interpolymers are anionicC₂-C₄ cellulose esters having an acid number from about 30 to about 120.In a further embodiment, the cellulose ester interpolymers are anionicC₂ cellulose esters having an acid number from about 40 to about 100.The enteric coating can be comprised of a single preferred oxidizedcellulose ester or a mixture of cellulose ester interpolymers.

In the case of blends for enteric coating were the cellulose esterinterpolymers represent one or more components of the blend, in oneembodiment, the cellulose ester interpolymers are anionic C₂-C₄cellulose esters having an acid number from about 30 to about 120. In afurther embodiment, the cellulose ester interpolymers are anionic C₂cellulose esters having an acid number from about 40 to about 100. Theother components of the blend can be one or more of any water soluble,pH sensitive, or water insoluble polymer useful in enteric coatings.Examples of useful water soluble polymers include, but are not limitedto, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or methylcellulose. Examples of pH sensitive polymers include, but are notlimited to, cellulose acetate phthalate, cellulose acetate succinate,cellulose acetate trimellitate, or hydroxypropyl methyl cellulosephthalate. Examples of useful water insoluble polymers include, but arenot limited to, cellulose acetate, cellulose acetate propionate, orcellulose acetate butyrate. Those skilled in the art will recognize thatthe ratio of the blend components is dependent upon the individualformulation and the desired release rate of the therapeutic agent.Hence, a very broad range of blend components and component ratios iscontemplated.

In enteric coatings, the cellulose ester interpolymers or blends thereofand optional additives, are dissolved in a suitable solvent or mixtureof solvents. The solid core containing the therapeutic agent can becoated with these cellulose ester interpolymers solutions by a number ofprocesses well known to those skilled in the art such as fluidized bedor side vented pan coating processes. Examples of preferred solvents inthe present invention include alcohols, ketones, ethers, esters, andchlorinated hydrocarbons. Specific examples of these solvents include,but are not limited to, ethanol, acetone, 2-butanone, 2-pentanone, ethylacetate, propyl acetate, propyl ether, tetrahydrofuran, methylenechloride, chlorobenze, and the like. Optionally, these solvents maycontain from about 0.01 to about 50 wt % H₂O. The optional additivesinclude plasticizers, pigments, colorants, stabilizers, antioxidants,and waxes. Commonly used plasticizers include, but are not limited to,diethyl phthalate, dioctyl phthalate, triacetin, polyethylene glycol,and the like.

In one embodiment, the invention provides a method for treating a mammalin need thereof, with at least one therapeutic agent, which comprisesadministering to said mammal an oral pharmaceutical compositioncomprising a therapeutic agent having coated thereon or admixedtherewith a composition comprising a cellulose ester interpolymerwherein the C2 and C3 positions of each of the anhydroglucose units ofthe cellulose ester interpolyer are in the alcohol oxidation state, andcomprising anhydroglucose units

whereinR₁, R₂, R₃, R₄, and R₅ are independently selected from the groupconsisting of hydrogen and C₂-C₁₂ acyl groups, wherein at least one ofR₁, R₂, R₃, R₄, and R₅ is a C₂-C₁₂ acyl group; and,X is formyl, hydroxymethylene, aminomethyl, R₆—NH—CH₂— or carboxy or amixture thereof, wherein R₆ is selected from the group consisting ofalkyl, aryl, or alkylene-aryl, provided when at least some of X iscarboxy, the acid number is greater than 10; wherein the anhydroglucoseunits A and B comprise greater than 65% of the total anhydroglucoseunits of the cellulose portion of the cellulose ester interpolymer.

In the case in which the cellulose ester interpolymers are used asrelease rate modifiers of therapeutic agents from a solid core, thepreferred cellulose ester interpolymers are anionic, cationic, orzwitterionic C₂-C₈ cellulose esters. The most preferred cellulose esterinterpolymers are anionic C₂-C₄ cellulose esters having an acid numberfrom about 40 to about 120. As a release rate modifier, the modifier maybe a single preferred oxidized cellulose ester or a mixture of celluloseester interpolymers.

The cellulose ester interpolymers can be incorporated into the solidcore along with the therapeutic agent by a number of techniques wellknown to those skilled in the art. The solid core comprises one or moreoxidized cellulose ester, a pharmaceutically acceptable carrier, and atherapeutically effective amount of therapeutic agent. A film coatingoptionally surrounds the solid core. These solid cores can be in theform of, by way of example and without limitation, chewable bar,capsule, fiber, film, gel, granule, chewing gum, pellet, powder, tablet,stick, strip and wafer.

Intended routes of administration include oral or buccal. The solid coreformulations of the present invention are generally administered withpharmaceutically acceptable carriers or diluents, the proportion andnature of which are determined by the solubility and chemical propertiesof the therapeutic agents selected, the chosen dosage form, and standardpharmaceutical practice. Solid oral forms may contain conventionalexcipients, for instance: lactose, sucrose, magnesium stearate, resinsand like materials, flavoring, coloring, buffering, preserving, orstabilizing, agents.

As used herein, “release rate modifier” means cellulose esterinterpolymers which serve to modify the rate of release of therapeuticagents. The release rate modifier will assist in providing a controlledrelease of the therapeutic agent and can cooperate with other componentsin the formulation to provide a delayed, sustained, timed, pH dependent,targeted, or further controlled delivery of the therapeutic agent. Thus,in a further embodiment, the invention provides a method wherein thecellulose ester interpolymer modifies ordinary release rate profile ofthe therapeutic agent. In this context, the point of thegastrointestinal tract where a given therapeutic agent is absorbed willbe modified.

In this context, we expect that inclusion of certain solubilityenhancers in the solid core along with the cellulose ester interpolymersmay serve to provide for the increased solubility and oralbioavaliability of the therapeutic agents. The solubility enhancer canbe any agent which will aid in increasing the water solubility of thetherapeutic agent. The solubility enhancer can be incorporated with theoxidized cellulose ester release modifier and therapeutic agent as aphysical mixture. Alternatively, in certain instances, the solubilityenhancer and therapeutic agents can be incorporated into the solid corewith the oxidized cellulose ester release modifier as a complex or asvesicles. Examples of solubility enhancers include water-solublecyclodextrins, cyclodextrin derivatives, andpolyethyleneoxide-polypropyleneoxide block copolymers. Preferredcyclodextrin derivatives include hydroxybutenyl cyclodextrins (U.S. Pat.No. 6,479,467, incorporated herein by reference) and sulfohydroxybutenylcyclodextrins (U.S. Pat. No. 6,610,671, incorporated herein byreference). Preferred polyethyleneoxide-polypropyleneoxide blockcopolymers are available from BASF Corporation under the trade namePluronics.

In particular, the pharmaceutical compositions of the present inventionsmay include water-soluble CD or CD derivatives. The CD or CD derivativeis or is derived from a CD of any ring size, including but not limitedto α, β, or γ-cyclodextrins. In some embodiments, the hydroxybutenylcyclodextrin is hydroxybutenyl-α, β, or γ-cyclodextrin. In someembodiments, the hydroxybutenyl cyclodextrin derivative is sulfonatedhydroxybutenyl-α, β, or γ-cyclodextrin. In some embodiments, thehydroxybutenyl cyclodextrin is hydroxybutenyl-β-cyclodextrin and thehydroxybutenyl cyclodextrin derivative is sulfonatedhydroxybutenyl-β-cyclodextrin.

In some embodiments, the hydroxybutenyl-β-cyclodextrins have a molarsubstitution (MS, wherein MS is the total number of substitutentsattached to the CD) from about 1 to about 12. In some embodiments, thehydroxybutenyl-β-cyclodextrins are hydroxybutenyl-β-cyclodextrins with aMS from about 3 to about 10. In some embodiments, thehydroxybutenyl-β-cyclodextrins are water-soluble and have a MS fromabout 4 to about 7. In some embodiments, thehydroxybutenyl-β-cyclodextrins are water-soluble and have a MS fromabout 4.5 to about 5.5. In some embodiments, thehydroxybutenyl-β-cyclodextrins are water-soluble and have a MS of about5.

In some embodiments, the hydroxybutenyl cyclodextrin derivatives aresulfonated hydroxybutenyl-α, β, or γ-cyclodextrins. In some embodiments,the sulfonated hydroxybutenyl cyclodextrins are sulfonatedhydroxybutenyl-β-cyclodextrins comprising at least one hydroxybutylsulfonate substitutent. In some embodiments, the sulfonatedhydroxybutenyl-β-cyclodextrins have a MS of hydroxybutyl sulfonate fromabout 0.02 to about 7. In some embodiments, thehydroxybutenyl-β-cyclodextrins have a MS of hydroxybutyl sulfonate fromabout 0.1 to about 2. In the case of sulfonated hydroxybutenyl-α, β, orγ-cyclodextrins, those skilled in the art will recognize that thesecyclodextrin ethers contain both hydroxybutenyl substitutents andhydroxybutyl sulfonate substitutents. In this case, the total MS isprovided by the sum of the hydroxybutenyl MS and the hydroxybutylsulfonate. In some embodiments, the total MS is from about 0.02 to about12. In some embodiments, cyclodextrin ethers containing at least onehydroxybutyl sulfonate substitutent optionally further compriseadditional alkyl, sulfinate, or disulfonate substitutents.

In some cases, the cellulose ester interpolymers may serve as solubilitymodifiers of one or more therapeutic agents in the solid core.

In one embodiment, the cellulose ester interpolymers act as solubilitymodifiers of therapeutic agents, the preferred cellulose esterinterpolymers are anionic, cationic, or zwitterionic C₂-C₁₂ celluloseesters. The more preferred cellulose ester interpolymers are one or moreanionic C₂-C₈ cellulose esters having an acid number from about 40 toabout 120. The more preferred cellulose ester interpolymers are one ormore anionic C₂-C₄ cellulose esters having an acid number from about 40to about 120. In the case where the cellulose ester interpolymers servesas a solubility modifier in the solid core, the oxidized cellulose esterand the therapeutic agent can be combined in the solid core as aphysical mixture.

Alternatively, in the case where the cellulose ester interpolymersserves as solubility modifiers in the solid core, the therapeutic agentsand the oxidized cellulose ester can be combined to form blends,microspheres, nanospheres, or hydrogels prior to incorporation into thesolid core. The blends can be formed by first dissolving the celluloseester interpolymers in an appropriate solvent and dissolving thetherapeutic agents in the same or second solvent. A blend is then formedby mixing the two solutions followed by removal of the solvents bymethods known to those skilled in the art. The microspheres,nanospheres, or hydrogels can be formed by an emulsification-interfacialcross-linking process or by complexation between oppositely chargedmacromolecules. In the case of complexation between oppositely chargedmacromolecules, the complimentary charged macromolecule to the celluloseester interpolymers may be the complimentary charged cellulose esterinterpolymer. For example, an anionic C₂-C₁₂ cellulose esters having anacid number from about 40 to about 120 may be complexed with a cationicC₂-C₁₂ cellulose esters of the present invention in the presence of atherapeutic agent forming the desired microsphere or nanosphere. In thecase of a zwitterionic C₂-C₁₂ cellulose ester, the complexation leadingto formation of the desired microsphere or nanosphere may result frominternal ionic interactions. It is not necessary that the complimentarycharged macromolecule be an oxidized cellulose ester. Examples, but notlimited to, of complimentary charged macromolecules for anioniccellulose ester interpolymers are chitosans having from about 40% toabout 60% N-acetyl groups and derivatives thereof. Examples, but notlimited to, of complimentary charged macromolecules for cationiccellulose ester interpolymers are carboxymethyl cellulose, alginates,xanthan, hyaluronic acid, and derivatives thereof. When necessary, themicrospheres, nanospheres, or hydrogels can be isolated as powders bytechniques known to those skilled in the art such as spray frying orfreeze drying.

As used herein, “solubility modifier” means cellulose esterinterpolymers which serve to modify the solubility of therapeutic agentswhich are otherwise poorly water-soluble. In certain instances, thecellulose ester interpolymers may act as both a release rate modifierand as a solubility modifier of therapeutic agents. Thus, in a furtherembodiment, the invention provides a method for increasing thesolubility of the at least one therapeutic agent, thereby increasing itsoral bioavailability.

In another aspect of the invention, the cellulose ester interpolymersincorporated as a solid core component can function as a bioadhesive. Abioadhesive is defined as a material that adheres or interacts stronglywith biological surfaces such as mucous membranes or skin tissue. Thenet effect is to localize the therapeutic agent thereby increasing itsbioavaliability. The preferred cellulose ester interpolymers areanionic, cationic, or zwitterionic C₂-C₁₂ cellulose esters. Morepreferred are anionic, cationic, or zwitterionic C₂-C₈ cellulose esters.

With regard to drug delivery compositions, therapeutic agent means anybioactive agent capable of eliciting the required or desired therapeuticresponse from a patient when administered orally or bucally. A patientis any living human or animal. Examples of therapeutic agents includeantineoplastics, antiviral agents, antidiabetic agents, antidepressants,antifungal agents, antibacterial agents, antimigrane, antiprotozoalagents, antisense agents, androgens, estrogens, sedatives, serotoninantagonists, narcotic antagonists, narcotic agonists, proteins,peptides, steroids, tranquilizers, antipsychotics, antidepressants,antiallergics, antianginals, antiarthritics, antiasthmatics,antidiabetics, antidiarrheal drugs, anticonvulsants, antigout drugs,antihistamines, antipruritics, anticoagulants, emetics, antiemetics,antispasmondics, appetite suppressants, neuroactive substances,neurotransmitter agonists, antagonists, receptor blockers and reuptakemodulators, beta-adrenergic blockers, calcium channel blockers,disulfarim and disulfarim-like drugs, muscle relaxants, analgesics,antipyretics, stimulants, anticholinesterase agents, parasympathomimeticagents, hormones, anticoagulants, antithrombotics, thrombolytics,immunoglobulins, immunosuppressants, hormone agonists/antagonists,vitamins, antimicrobial agents, antineoplastics, antacids, digestants,laxatives, cathartics, antiseptics, diuretics, disinfectants,fungicides, ectoparasiticides, antiparasitics, heavy metals, heavy metalantagonists, chelating agents, gases and vapors, alkaloids, salts, ions,autacoids, digitalis, cardiac glycosides, antiarrhythmics,antihypertensives, vasodilators, vasoconstrictors, antimuscarinics,ganglionic stimulating agents, ganglionic blocking agents, neuromuscularblocking agents, adrenergic nerve inhibitors, anti-oxidants, vitamins,cosmetics, anti-inflammatories, wound care products, antithrombogenicagents, antitumoral agents, antithrombogenic agents, antiangiogenicagents, anesthetics, antigenic agents, wound healing agents, plantextracts, growth factors, emollients, humectants,rejection/anti-rejection drugs, spermicides, conditioners, antibacterialagents, antifungal agents, antiviral agents, antibiotics, tranquilizers,cholesterol-reducing drugs, agents for treatment of Parkinson's orAlzheimer's disease, vitamins/nutritional factors, antitussives,histamine-blocking drugs, monoamine oxidase inhibitor, orpharmaceutically acceptable salts or metabolites of any of theforegoing. In some embodiments, the pharmaceutically active drugs arehydrophobic, poorly water-soluble drugs.

Non-limiting examples of therapeutic agents include orally-active formsof the following: abacavir, acarbose, acebutolol, acetazolamide,acetohexamide, acrivastine, acutretin, acyclovir, alatrofloxacin,albendazole, albuterol, alclofenac, alendronate, allopurinol, aloxiprin,alprazolam, alprenolol, alprostadil, amantadine, amiloride,aminoglutethimide, amiodarone, amitriptyline, amlodipine, amodiaquine,amoxapine, amoxapine, amphetamine, amphotericin, amprenavir, aminone,amsacrine, amyl nitrate, amylobarbital, amylobarbitone, anastrozole,arzoxifene, aspirin, astemizole, atenolol, atorvastatin, atovaquone,atropine, auranofin, azapropazone, azathioprine, azelastine,azithromycin, baclofen, barbital, barbitone, becaplermin, beclamide,beclomethasone, bendrofluazide, benethamine, benethamine penicillin,benezepril, benidipine, benorylate, bentazepam, benzhexyl, benznidazole,benzonatate, benztropine, bephenium hydroxynaphthoate, betamethasone,bexarotene, bezafibrate, bicalutamide, bifonazole, biperiden, bisacodyl,bisanthrene, bovine growth hormone, bromazepam, bromfenac,bromocriptine, bromocriptine mesylate, bromperidol, brompheniramine,brotizolam, budesonide, bumetanide, bupropion, busulphan, butenafine,butobarbital, butobarbitone, butoconazole, butoconazole nitrate,calcifediol, calciprotiene, calcitonin, calcitriol, cambendazole,camidazole, camptothecan, camptothecin, candesartan, capecitabine,capsacin, capsaicin, captopril, carbamazepine, carbimazole,carbinoxamine, carbromal, carotenes, cefazolin, cefoxitin sodium,celecoxib, cephadrine, cephalexin, cerivistatin, cetrizine,chlopheniramine, chlophenisamine, chloproguanil, chlorambucil,chlordiazepoxide, chlormethiazole, chloroquine, chlorothiazide,chlorpromazine, chlorpropamide, chlorprothiocene, chlorprothixene,chlorthalidone, cholecalciferol, cilostazol, cimetidine, cinnarizine,cinoxacin, ciprofloxacin, cisapride, citalopram, citrizine,clarithromycin, clemastine, clemastine fumarate, clemizole, clenbuterol,clinofibrate, clioquinol, clobazam, clofazimine, clofibrate, clomiphene,clomipramine, clonazepam, clopidrogel, clotiazepam, clotrimazole,cloxacillin, clozapine, codeine, conjugated estrogens, cortisoneacetate, cortisone acetate, cromalyn sodium, cromoglicate, cromolyn,cyclizine, cyclosporin, cyproheptadine, dacarbazine, danazol,dantrolene, darodipine, decoquinate, delavirdine, demeclocycline,desoxymethasone, dexamphetamine, dexanabinol, dexchlopheniramine,dexfenfluramine, dextropropyoxyphene, diamorphine, diazepam, diazoxide,dichlorophen, diclofenac, dicloxacillin, dicoumarol, dicumarol,didanosine, diethylpropion, diflunisal, digitoxin, digoxin, dihydroepiandrosterone, dihydrocodeine, dihydroergotamine, dihydroergotaminemesylate, dihydrotachysterol, diiodohydroxyquinoline, dilitazem,diloxanidefuroate, dimenhydrinate, dinitolmide, diphenhydramine,diphenooxylate, diphenylimidazole, diphenylpyrallin, dipyridamole,dirithromycin, disopyramide, divalproen, docetaxel, doconazole,docusate, dolasetron, domperidone, donepezil, doxercalciferol,doxazosin, doxycycline, doxorubicin, droloxifene, dronabinol,droperidol, dutasteride, econazole, econazole nitrate, editronate,efavirenz, elanapril, ellipticine, enalapril, enkephalin, enoxacin,enoximone, enrofloxacin, epalrestate, eperisone, ephedrine, eposartan,eposartan losartan, ergocalciferol, ergotamine, erythromycin,erythropoietin, essential fatty acids, estramustine, ethacrynic acid,ethambutol, ethinamate, ethinyloestradiol, ethionamide, ethopropazine,ethotoin, etodolac, etoperidone, etoposide, etretinate, exemestane,fadrozole, famcyclovir, famotidine, felbamate, felodipine, fenbendazole,fenbufen, fenfluramine, fenofibrate, fenolclopam, fenoldopam,fenoprofen, fenoprofen calcium, fentanyl, fenticonazole, fexofenadine,finasteride, flecamide, fluconazole, flucortolone, flucytosine,fludrocortisone, flunanisone, flunarizine, flunisolide, flunitrazepam,fluopromazine, fluoxetine, fluoxymisterone, flupenthixol decanoate,flupentixol, flupentixol decanoate, fluphenazine, fluphenazinedecanoate, flurazepam, flurbiprofen, flurithromycin, fluticasone,fluvastatin, formestane, foscarnet, fosinopril, fosphenyloin,frovatriptan, frusemide, fumagillin, furazolidone, furosemide,furzolidone, gabapentin, gancyclovir, gemfibrozil, gentamycin,glibenclamide, gliclazide, glipizide, glucagon, glybenclamide,glyburide, glyceryl trinitrate, glymepiride, glymepride, granisetron,granulocyte stimulating factor, grepafloxacin, griseofulvin, goserelin,guanabenz, halofantrine, haloperidol, hydrocortisone, hyoscyamine,ibufenac, ibuprofen, imipenem, idarubicin, indinavir, indivir,indomethacin, insulin, interferon, pegylated interferon, interleukin-3,irbesartan, irinotecan, isoconazole, isosorbide dinitrate, isosorbidemononitrate, isotretinoin, isoxazole, isradipine, itraconazole,ivermectin, ketoconazole, ketoprofen, ketorolac, ketotifen, labetalol,lamivudine, lamotrigine, lanatoside C, lanosprazole, leflunomide,letrozole, levofloxacin, levothyroxine, lisinopril, linezolide,lombazole, lomefloxacin, lomustine, loperamide, lopinavir, loratadine,lorazepam, lorefloxacin, lormetazepam, losartan, lotrimin, lovastatin,L-thryroxine, lysuride, lysuride maleate, maprotiline, mazindol,mebendazole, meclofenamic acid, meclozine, medazepam, medigoxin,medroxyprogesterone acetate, mefenamic acid, mefloquine, megesterolacetate, melonicam, meloxicam, melphalan, mepacrine, mepenzolatebromide, meprobamate, meptazinol, mercaptopurine, mesalazine,mesoridazine, mesoridiazine, mestranol, metformin, methadone,methaqualone, methoin, methotrexate, methoxsalen, methsuximide,methylphenidate, methylphenobarbital, methylphenobarbitone,methylprednisolone, methyltestosterone, methysergide, methysergidemaleate, metoclopramide, metolazone, metoprolol, metronidazole,mianserin, miconazole, midazolam, miglitol, minoxidil, mitomycin,mitotane, mitoxantrone, mofetil, molindone, montelukast, morphine,mortriptyline, moxifloxacin, mycophenolate, nabumetone, nadolol,nalbuphine, nalidixic acid, naproxen, naratriptan, natamycin, nedocromilsodium, nefazodone, nelfinavir, nerteporfin, neutontin, nevirapine,nicardipine, nicotine, nicoumalone, nifedipine, nilutamide, nimesulide,nimodipine, nimorazole, nisoldipine, nitrazepam, nitrofurantoin,nitrofurazone, nizatidine, non-essential fatty acids, norethisterone,norfloxacin, norgestrel, nortriptyline HCl, nystatin, oestradiol,ofloxacin, olanzapine, omeprazole, ondansetron, oprelvekin, ornidazole,orconazole, ospemifene, oxacillin, oxamniquine, oxantel, oxantelembonate, oxaprozin, oxatomide, oxazepam, oxcarbazepine, oxfendazole,oxiconazole, oxmetidine, oxprenolol, oxybutynin, oxyphenbutazone,oxyphencylcimine, paclitaxel, pamidronate, paramethadione, parconazole,paricalcitol, paroxetine, penicillins, pentaerythritol tetranitrate,pertazocine, pentobarbital, pentobarbitone, pentoxifylline,perchloperazine, perfloxacin, pericyclovir, perphenazine, perphenazinepimozide, phenacemide, phenbenzamine, phenindione, pheniramine,phenobarbital, phenobarbitone, phenoxybenzamine, phensuximide,phentermine, phenylalanine, phenylbutazone, phenyloin, physostigmine,phytonodione, pimozide, pindolol, pioglitazone, piroxicam, pizotifen,pizotifen maleate, posaconazole, pramipexol, pramipexole, pranlukast,pravastatin, praziquantel, prazosin, prednisolone, prednisone,pregabalin, primidone, probenecid, probucol, procarbazine,prochlorperazine, progesterone, proguanil, propofol, propranolol,propylthiouracil, pseudoephedrine, pyrantel, pyrantel embonate,pyridostigmine, pyrimethamine, quetiapine, quinapril, quinidine,quinine, rabeprazole, raloxifene, ranitidine, ravuconazole, recombinanthuman growth hormone, refocoxib, remifentanil, repaglinide, reserpine,residronate, retinoids, ricobendazole, rifabutin, rifabutine,rifampicin, rifampin, rifapentine, rimantadine, rimexolone, risperodone,ritonavir, rizatriptan, rizatriptan benzoate, ropinirole, rosiglitazone,roxatidine, roxithromycin, salbutamol, salmon calcitonin (sCT),saquinavir, selegiline, sertindole, sertraline, sibutramine, sildenafil,simvastatin, sirolimus, sodium cefazoline, somatostatin, sparfloxacin,spiramycins, spironolactone, stanozolol, stavudine, stavueline,stiboestrol, sulconazole, sulfabenzamide, sulfacetamide, sulfadiazine,sulfadoxine, sulfafurazole, sulfarnerazine, sulfamethoxazole,sulfapyridine, sulfasalazine, sulindac, sulphabenzamide, sulphacetamide,sulphadiazine, sulphadoxine, sulphafurazole, sulphamerazine,sulphamethoxazole, sulphapyridine, sulphasalazine, sulphin-pyrazone,sulpiride, sulthiame, sumatriptan, tacrine, tacrolimus, tamoxifen,tamsulosin, targretin, tazarotene, telmisartan, temazepam, teniposide,terazosin, terbinafine HCl, terbutaline, terbutaline sulfate,terconazole, terenadine, terfenadine, testolactone, testosterone,tetracycline, tetrahydrocannabinol, tetramisole, thiabendazole,thioguanine, thioridazine, tiagabine, tibolone, ticlidopine,ticlopidine, tiludronate, timolol, tinidazole, tioconazole, tirofibran,tizanidine, tolazamide, tolbutamide, tolcapone, tolmetin, tolterodine,topiramate, topotecan, toremifene, tramadol, trazodone, tretinoin,triamcinolone, triamterene, triazolam, trifluoperazine, trimethoprim,trimipramine, troglitazone, tromethamine, tropicamide, trovafloxacin,tubulazole, tumor necrosisi factor, undecenoic acid, ursodeoxycholicacid, valacylcovir, valconazole, valproic acid, valsartan, vancomycin,vasopressin, venlafaxine HCl, verteporfin, vigabatrin, vinblastine,vincristine, vinorelbine, vitamin A, vitamin B2, vitamin D, vitamin Eand vitamin K, vitamin K5, vitamin K6, vitamin K7, vitamin K-S (II),voriconazole, zafirlukast, zileuton, ziprasidone, zolmitriptan,zolpidem, and zopiclone.

In some instances, it is believed that the cellulose ester interpolymersof the present invention may function as a therapeutic agent. Inparticular, due to the high concentration and localization of ioniccharge, it is possible that the cellulose ester interpolymers may beeffective in decreasing or preventing the frequency of transmission ofthe human immunodeficiency virus, herpes viruses, or sexuallytransmitted bacterial infections through administration to a human of ananti-human immunodeficiency virus amount or an anti-herpes virus amountor an anti-bacterial amount of the oxidized cellulose ester. Theanti-viral or antibacterial oxidized cellulose ester may be used eitheralone or in combination with a pharmaceutically acceptable carrier ordiluent. Unlike the dextran sulfates or cellulose acetate phthalatescurrently utilized for this purpose (J. Experimental Med. 2000, 192,1491-1500; WO 01/05377 A1, BMC Infectious Diseases, 2002, 2:6; BMCInfectious Diseases, 2001, 1:17; Antimicrobial Agents and Chemotherapy,2000, 44, 3199-3202; U.S. Pat. No. 6,165,493; Antimicrobial Agents andChemotherapy, 1990, 34, 1991-1995), the ionic charge of the celluloseester interpolymers of the present invention is covalently attached tothe backbone of the polysaccharide via a carbon-carbon bond and is notsusceptible to hydrolysis which will render the polysaccharidederivative inactive. This asset may allow the cellulose esterinterpolymers to be more conveniently formulated into a stableformulation with a long shelf and use life. The preferred celluloseester interpolymers are anionic, cationic, or zwitterionic C₂-C₁₂cellulose esters. More preferred cellulose ester interpolymers areanionic C₂-C₈ cellulose esters having an acid number from about 30 toabout 200. The most preferred anionic cellulose esters have an acidnumber from about 60 to about 150.

This invention also relates to thermoplastic compatibilizers comprisingthe cellulose ester interpolymers of the present invention. Whenincorporated into blends of two or more polymers in which one of thepolymers is a cellulose ester, it is anticipated that the oxidizedcellulose ester thermoplastic compatibilizer will improve themiscibility between the two polymers by providing a favorable enthalpiceffect via ionic interactions. Likewise, the oxidized cellulose esterthermoplastic compatibilizers are anticipated to improve the interfacialadhesion in cellulose ester natural fiber composites by providing afavorable enthalpic effect via ionic interactions. Furthermore, incertain instances, it is anticipated that the oxidized cellulose esterthermoplastic compatibilizers will increase the biodegradation rate ofthe blend or composite.

As thermoplastic compatibilizers, the preferred cellulose esterinterpolymers are anionic, cationic, or zwitterionic C₂-C₁₂ celluloseesters. More preferred cellulose ester interpolymers are anionic C₂-C₄cellulose esters having an acid number from about 40 to about 120. Themost preferred anionic cellulose esters have an acid number from about40 to about 90 and the substitutent type matches the neutral celluloseester component in the polymer blend or composite.

The anionic cellulose esters can be used in either the acid form or whenthe anionic functionality has been neutralized salt. In one embodiment,the anionic cellulose ester is neutralized with a base selected fromNaOH, KOH, Ca(OH)₂, CaCO₃, Ca(OAc)₂, Mg(OH)₂, MgCO₃, or Mg(OAc)₂. Inanother embodiment, the anionic cellulose ester has been neutralized andis incorporated into the blend or composite as the Ca or Mg salt.

It is anticipated that the cellulose ester interpolymers of theinvention can improve the compatibility in blends and the interfacialadhesion in composites. In one embodiment, the amount of the oxidizedcellulose ester is from about 1 to about 15 wt % based on total weightof the mixture. In another embodiment, the amount of oxidized celluloseester is from about 2 to about 5 wt % based on total weight of themixture.

The neutral cellulose esters that can be used with the oxidizedcellulose ester thermoplastic compatibilizer are secondary celluloseesters such as cellulose acetate, cellulose acetate propionate, andcellulose acetate butyrate. These cellulose esters are commerciallyavailable from Eastman Chemical Company, Inc., Kingsport, Tenn., U.S.A.

In one embodiment, the neutral cellulose esters useful in the presentinvention have a Mw from about 5,000 to about 400,000 as measured byGPC. In another embodiment, the Mw is from about 100,000 to about300,000. In a further embodiment, the Mw is from about 125,000 to about250,000. In one embodiment, the DS of the neutral cellulose estersuseful herein is from about 0.7 to about 3.0. in another embodiment, theDS is from about 1.7 to about 2.8. In a further embodiment, the DS isfrom about 1.9 to about 2.6. The preferred Mw and DS depend upon theapplication in which the cellulose esters are used. In certain cases,the DS of each acyl substituent will influence the properties ofcellulose mixed ester. Examples of esters of cellulose include cellulosetriacetate (CTA), cellulose acetate (CA), cellulose acetate propionate(CAP), cellulose acetate butyrate (CAB), and the like.

The second polymer component in the polymer blends containing theoxidized cellulose ester thermoplastic compatibilizer is selected frompolyesters, polycarbonates, cellulose esters, polyalkanoates,polyamides, polyesteramides.

The oxidized cellulose ester thermoplastic compatibilizer and theneutral cellulose esters can be in the form of a powder, bead, pellet,or fiber prior to incorporation into natural fiber composites. Mostpreferred is when the oxidized cellulose ester thermoplasticcompatibilizer and the neutral cellulose esters are in the form of afiber.

Often, the oxidized cellulose ester thermoplastic compatibilizer and theneutral cellulose esters are plasticized either in the fiber form priorto incorporation into the composite or during formation of thecomposite. Examples of preferred plasticizers include phthalates (e.g.diethyl or dibutyl phthalate), glycerol, triacetin, citrate esters (eg.triethylcitrate), aliphatic diesters (e.g. dioctyl adipate), phosphates(e.g. triphenyl phosphate), low molecular weight polyethylene glycols,esters of polyethylene glycols, and carbohydrate or polyol esters (SeeU.S. Ser. No. 10/340,012, filed Jan. 10, 2003 and Published U.S.Application No. 2003/0171458, incorporated herein by reference). Themost preferred plasticizers are carbohydrate or polyol esters. Selectionof the proper plasticizer and the amount of plasticizer is based uponthe compatibility of the plasticizer with the cellulose ester and on thedesired properties in the finished part. In this regard, it is importantto note that the compatibility of each plasticizer will vary with eachcellulose ester. For example, dioctyl adipate has poor compatibilitywith cellulose acetates, but good compatibility with most celluloseacetate butyrates.

It is preferred that the natural fibers of the composite structurecomprise hemp, sisal, flax, kenaf, cotton, abaca, jute, kapok, papyrus,ramie, coconut (coir), wheat straw, rice straw, hardwood pulp, softwoodpulp, and wood flour. More preferably, the natural cellulose fiber isselected from the group consisting of hemp, sisal, flax, kenaf, cotton,jute and coir. A suitable fiber length for the natural cellulose fibercomponent of this invention would be 0.01 to 10.2 cm.

It is preferred that the composite structure be comprised of about atleast 50 wt % natural fiber. More preferable is when the natural fiberis from about 60 to about 75 wt % with the balance being comprised ofthe oxidized cellulose ester thermoplastic compatibilizer and theneutral cellulose esters.

Those skilled in the art will understand that the most preferredcompositions, the preferred method of forming the composites, and thepreferred processing conditions will depend on the intended applicationsand desired physical properties. As such, a broad composition range andprocessing window is anticipated.

This invention also relates to the use of the cellulose esterinterpolymers of this invention as film forming agents, thickeningagents, rheology modifiers, wetting agents, and dispersing agents inpersonal care formulations. Examples of personal care formulationsinclude, but are not limited to, hair care, nail polish, skin gloss andmakeup, lipstick and lip gloss, deodorants, mascara, and eyelinerformulations.

In personal care compositions, the preferred cellulose esterinterpolymers are anionic, cationic, or zwitterionic C₂-C₁₂ celluloseesters. More preferred cellulose ester interpolymers are anionic,cationic, or zwitterionic C₂-C₄ cellulose esters. The more preferredoxidized cellulose esters are anionic C₂-C₄ cellulose esters having anacid number of about 40 to about 120. Those skilled in the art willrecognize that the most preferred oxidized cellulose esters will bedetermined by the particular personal care formulation and the intendeduse.

In many personal care formulations, typically, some or all of thecarboxyl groups of the preferred cellulose ester interpolymers areneutralized to provide increased solubility or clarity of thedispersion, and to provide continuous film formation. Neutralization canbe accomplished by using an inorganic base such as sodium hydroxide,potassium hydroxide, ammonium hydroxide, or combinations thereof.Organic bases may also be used and include for example,monoethanolamine, diethanolamine, triethanolamine, 2-amino-2-methylpropanol (AMP), monoisopropaolamine, triisopropanolamine, andcombinations thereof.

The degree of neutralization (percentage of acid groups that areneutralized with base) varies depending on the other ingredients in thepersonal care formulations, and the intended function and/or performancecharacteristics of the personal care formulations. Generally, the degreeof neutralization is from about 20 to 100%. The preferred neutralizationis from about 40 to 90%; and most preferred is from about 50 to 80%.

Many, if not all, personal care formulations contain other resins andadditives to modify and enhance the performance of the personal careformulation. The preferred amount of each additive in highly dependentupon the particular application and hence, a very broad range isanticipated.

Examples of resins that can be included in personal care formulationsinvolving the cellulose ester interpolymers of the present inventioninclude, but are not limited to, cellulose nitrate, the ethyl,isopropyl, or n-butyl esters of poly(methylvinylether/maleic acid),polyvinyl pyrrolidone (PVP), polyvinyl caprolactam, polyvinylpyrrolidone/vinyl acetate, copolymers of vinyl pyrrolidone and methylmethacrylate, copolymers of vinyl pyrrolidone and dimethylaminopropylmethacrylamide, methacrylate/methacrylic acid copolymer,poly(ethylacrylate/acrylic acid/N-tert-butyl acrylamide), PVP/ethylmethacrylate/methacrylic acid terpolymer,PVP/vinylcaprolactam/dimethylaminopropyl methacrylamide terpolymer,poly(vinyl acetate/crotonic acid), vinyl acetate/crotonates/vinylneodecaoate copolymer, polyvinyl alcohol (PVA), copolymers of PVA andcrotonic acid, copolymers of PVA and maleic anhydride, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl guar gum, sodiumpolystyrene sulfonate, octylacrylamide/acrylate/butylaminoethylmethacrylate copolymers, sulfopolyesters, and mixtures thereof.

Due to the effectiveness of the cellulose ester interpolymers of thepresent invention to act as a dispersing agent, the resins that can beused with preferred cellulose ester interpolymers in personal carecompositions can be substantially hydrophobic. Examples of suchhydrophobic resins include, but are not limited to, neutral celluloseesters such as cellulose acetate propionate or cellulose acetatebutyrate, waxes; silicones; fluorocarbons; UV absorbers;photoinitiators; chlorinated and nonchlorinated polyolefins;hydroxy-functional resins such as acrylics, polyesters, and polyethers;acrylate-functional resins such as acrylated acrylics, acrylatedpolyesters, acrylated polyethers, acrylated polyurethanes, and acrylatedepoxies; amine-modified acrylated acrylics, polyesters and polyethers;unsaturated polyesters; allyl functional polymers; aminoplast resins,and the like.

Examples of additives include, but or not limited to, plasticizers,coalescing agents, silicones, emollients, emulsifiers, lubricants,penetrants such as various lanolin compounds, protein hydrolysates, orother protein derivatives, viscosity increasing and decreasing agents,ethylene adducts and polyoxyethylene cholesterol, dyes, tints and othercolorants, perfumes or fragrances, preservatives, antifoaming agents,chelating agents, polymers and resins, conditioners, and the like.

A few examples of additives that can be included in personal careformulations involving the cellulose ester interpolymers of the presentinvention include, but are not limited to, polysiloxane polyethercopolymers, polysiloxane polydimethyl dimethylammonium acetatecopolymers, acetylated lanolin alcohols, lauryl dimethylamine oxide, alanolin-derived extract of sterol ester, lanolin alcohol concentrate, anisopropyl ester of lanolin fatty acid, sulfur rich amino acidconcentrate, oleyl alcohol, stearyl alcohol, stearamidopropyl dimethylmyristyl acetate, a polyol fatty acid, a fatty amido amine, guarhydroxypropyltrimethyl ammonium chloride, cetyl/stearyl alcohol, keratinprotein derivatives, isostearamidopropyl dimethylamine, stearamidopropyldimethylamine, an amino functional silicone, ethoxylated (30) castoroil, acetylated lanolin alcohol, fatty alcohol fraction of lanolin, amineral oil and lanolin alcohol mixture, high molecular weight ester oflanolin, N-vinylpyrrolidone/dimethylaminoethyl methacrylate copolymer,ethylene oxide adducts of soya sterol, stearic acid ester of ethoxylatedmethyl glucoside, sodium salt of polyhydroxycarboxylic acid,hydroxylated lanolin, cocamidopropyl dimethylamine lactate,cocamidopropyl dimethylamine propionate, cocamidopropyl morpholinelactate, isostearamidopropyl dimethylamine lactate, isostearamidopropylmorpholine lactate, oleamidopropyl dimethylamine lactate,linoleamidopropyl dimethylamine lactate, a stearamidopropyldimethylamine lactate, ethylene glycol monostearate and propylene glycolmixture, stearamidopropyl dimethylamine lactate, acetamidemonoethanolamine, lactamide monoethanolamine, stearamidemonoethanolamine, behenalkonium chloride, a behenyl trimethyl ammoniummethosulfate and cetearyl alcohol mixture, cetearyl alcohol, tallowimidazaolinum methosulfate, mixed ethoxylated and propoxylated longchain alcohols, stearamidopropyl dimethylamine lactate, oleamine oxide,stearamide oxide, soya ethyldiammonium ethosulfate, ricinolamidopropylethyldimonium ethosulfate, N-(3-isostearamidopropyl)-N,N-dimethyl aminoglycolate, N-(3-isostearamidopropyl)-N,N-dimethyl amino gluconate,hydrolyzed animal keratin, ethyl hydrolyzed animal keratin,stearamidoethyl diethylamine, cocamidopropyl dimethylamine,lauramidopropyl dimethylamine, oleamidopropyl dimethylamine,palmitamidopropyl dimethylamine, stearamidopropyl dimethylamine lactate,avocado oil, sweet almond oil, grape seed oil, jojoba oil, apricotkernel oil, sesame oil, safflower oil, wheat germ oil, cocamidoaminelactate, ricinoleamido amine lactate, stearamido amine lactate,stearamido morpholine lactate, isostearamido amine lactate,isostearamido morpholine lactate, wheat germamido dimethylamine lactate,wheat germamidopropyl dimethylamine oxide, disodium isostearamidomonoethanolamine sulfosuccinate, disodium oleamide PEG-2 sulfosuccinate, disodium oleamide monoethanolamine sulfosuccinate, disodiumricinoleyl monoethanolamine sulfosuccinate, disodium wheat germamidomonoethanolamine sulfosuccinate, disodium wheat germamido PEG-2sulfosuccinate, stearamido amine, stearamido morpholine, isostearamidoamine, isostearamido morpholine, polyethylene glycol and distearates,synthetic calcium silicate, isostearic alkanolamide, ethyl ester ofhydrolyzed animal protein, blend of cetyl and stearyl alcohol withethoxylated cetyl or stearyl alcohol, amido amines, polyamido amine,propoxylated lanolin alcohol, isostearamide diethanolamine, andhydrolyzed collagen protein.

Examples of plasticizer additives include, but or not limited to,glycols, adipic esters, citrate esters, phthalate esters, carbohydrateor polyol esters, epoxidized vegetable oils, glycerine as well aspolymeric plasticizers. More preferred plasticizers in accordance withthe invention are, for example, diethylhexyladipate, dibutyl phthalate,dibutyl adipate, diethyl phthalate, diisobutyl adipate, diisononyladipate, n-butyl benzyl phthalate, 1,3-butylene glycol/adipic acidpolyester, tricresyl phosphate, benzyl benzoate, triphenyl phosphate,butyl stearate, triethyl citrate, tributyl citrate, tributyl acetylcitrate, camphor, epoxidized soybean oil, propylene glycol adipate,2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB), 2-amino-2-methylpropanol, and dibutyl sebacate. Other plasticizers include: Dimethiconecopolyol, PEG-6 capric/caprylic glyceride, phenyl trimethicone,propylene glycol, and dipropylene glycol.

Additional examples of additives include but are not limited toemulsifiers such as ethoxylated fatty alcohols and esters, ethoxylatedglycerides, dimethicone copolyol esters, glyceryl esters, hydrogenatedfatty glycerides, and the sodium salts of fatty acids. Preservativessuch as benzyl alcohol, methyl paraben, propyl paraben andimidazolidinylurea may also be used. Viscosity increasing agents thatmay be used include, methyl vinyl ether/maleic anhydride copolymer crosslinked with 1,9-decadiene, carbomers, acrylates/alkyl acrylate crosspolymers, the diethanolamide of a long chain fatty acid, fatty alcohols(for example, stearyl alcohol), cellulose gum, sodium chloride, andsodium sulfate. Viscosity decreasing agents that may be used include,for example, ethyl alcohol, glycerin, propylene glycol, andethoxydiglycol. The pH of personal care formulations may be adjustedusing pH adjusting agents such as citric acid, succinic acid, sodiumhydroxide, and triethanolamine. Colorants for use in personal careformulations are, for example, any of the Food, Drug and Cosmetics(FD&C) or Drug and Cosmetics (D&C) dyes. Bleaching agents such ashydrogen peroxide, perborate salts, persulfate salts, and percarbonatesalts may also be used. Perfume oils are also commonly found in manypersonal care products and may be used here. Chelating agents, such asethylenediamine tetraacetic acid (EDTA), may also be used.

The solvents that are useful for the personal care formulations of thepresent invention may be water, organic solvents, or mixtures thereof.In another aspect of the invention, the preferred oxidized celluloseester is dissolved in a compatible solvent, the resins or additives tobe incorporated are added, the oxidized cellulose ester is neutralizedto a given percent neutralization, and the solution inverted from asolvent continuous phase to an aqueous continuous phase. In this aspect,the cellulose ester interpolymers are also functioning as a dispersingagent in the personal care formulation. Alternatively, the preferredoxidized cellulose ester can be added directly to a solution containingwater, base, and organic solvent to obtain a solution.

Examples of organic solvents include, but are not limited to, alcohols,ketones, alkyl esters, polyols, ethers, aromatic hydrocarbons, andmixtures thereof. Examples of preferred organic solvents include, butare not limited to, ethanol, propanol, isopropanol, acetone, 2-butanone,methyl acetate, ethyl acetate, ethylene glycol monobutyl ether, ethyleneglycol monopropyl ether, diethylene monoethyl ether, toluene, xylene,and mixtures thereof.

As used herein, the term interpolymers include polymers comprising twoor more different monomer units. Interpolymers include copolymers andterpolymers. Further, interpolymer includes graft copolymers comprisinga cellulose polymer grafted to another polymer such as, but not limitedto, a polyethylene glycol.

As used herein, a random distribution of carboxy groups on a cellulosepolymer is defined as a cellulose polymer where the probability that ananhydroglucose unit having a C6 carboxy group is flanked on either orboth by anhydroglucose units having a C6 carboxy group is unpredictable.

As used herein, a C6 carboxy group refers to the 6 position of ananhydroglucose unit being a —CO₂H group wherein the —CO₂H includes thefree acid, salts of alkali earth metals, and ammonium and substitutedammonium salts.

As used herein, a C6 formyl group refers to the 6 position of ananhydroglucose unit being a —C(O)H group.

As used herein, a stable form of a cellulose ester interpolymer is onethat is stable to air hydrolysis, and capable of being isolated,characterized, and stored as a neat compound. Further, in this context,in one embodiment, the term “stable” means that it may be isolated andstored for up to six months with less than 5% hydrolysis of acylsubstituents.

As used herein, an amino substituted cyclic nitroxyl derivative refersto compounds having carbocyclic rings comprising a nitroxyl group as oneof the members of the ring, where no protons are alpha to the nitroxylgroup, and the amino substitutent is located at a position on thecarbocyclic ring other than alpha to the nitroxyl group. The size of thecarbocyclic ring is not particularly limited so long as the aminosubstituted cyclic nitroxyl derivative is operable to oxidize the C6position of anhydroglucose units of a cellulose or cellulose esterinterpolymer. In an embodiment, the carbocyclic ring contains six atoms.In another embodiment, the carbocyclic ring contains 5 atoms. The aminogroup may comprise an amine or a substituted amine wherein thesubstituent may comprise an alkyl group or a C₂-C₁₂ acyl group. Inanother embodiment, the amino substituted cyclic nitroxyl derivative isa 4-amino substituted 2,2,6,6-tetramethyl piperidin-1-oxyl derivative.In another embodiment, the amino substituted cyclic nitroxyl derivativeis 4-amino 2,2,6,6-tetramethyl piperidin-1-oxyl. In another embodiment,the amino substituted cyclic nitroxyl derivative is a 4-(C₁-C₄acylamido)-2,2,6,6-tetramethylpiperidin-1-oxyl. In another embodiment,the amino substituted cyclic nitroxyl derivative is4-acetamido-2,2,6,6-tetramethylpiperidin-1-oxyl.

As used herein, anhydroglucose units having C2, C3, and/or C6 positions“in the alcohol oxidation state” includes anhydroglucose units where theposition in the alcohol oxidation state is not an aldeyde, ketone, orcarboxy group. As a result, positions in the alcohol oxidation stateinclude hydroxyl groups and hydroxy group derivatives such as alkylethers and O-acyl groups.

For the purposes of this invention, “AN” means acid number; “MEK” meansmethyl ethyl ketone; “PM acetate” means propylene glycol monomethylether acetate; “diacetone alcohol” means 4-hydroxy-4-methyl-2-pentanone;“MPK” means methyl propyl ketone; “EB” means ethylene glycol monobutylether; “EP” means ethylene glycol monopropyl ether; “PM” means propyleneglycol monomethyl ether; “PB” means propylene glycol monobutyl ether;“EB acetate” means ethylene glycol monobutyl ether acetate; “PP” meanspropylene glycol monopropyl ether; “2-EH acetate” means2-ethyl-1-hexanol acetate; “EEP” means ethyl 3-ethoxypropionate; “MIBK”means methyl iso-butyl ketone; “MAK” means methyl amyl ketone; “IBIB”means iso-butyl iso-butyrate; Texanol® means2,2,4-trimethyl-1,3-pentanediol monoisobutyrate; “RDS” means relativedegree of substitution at the 3 hydroxyls of the anhydroglucose monomerof cellulose; “Eqs” means equivalents.

As used herein, an “alkyl” group, unless noted otherwise, preferablyrefers to a C₁-C₁₂ straight chain hydrocarbon group.

As used herein, the term “aryl” preferably refers to groups such asphenyl, napthyl, phenanthryl, biphenyl, etc.

As used herein, the term “hydroxymethylene” refers to a group of theformula —CH₂OH.

As used herein, the term “alkylenearyl” preferably refers to a C₁-C₁₂alkylene group having an aryl group attached.

EXAMPLES Examples 1-5

To a 5 L 5-neck round-bottom jacked-flask equipped with a mechanicalstirrer, reflux condenser, thermocouple, addition funnel, and atemperature controlled circulating bath was added a solution of 88%formic acid (See Table 1). The solution was chilled to 5° C. beforeadding 318 mL of Ac₂O over a 20 min period. To this solution, was added125 g of cellulose followed by a solution of 9.35 g of H₂SO₄ in 55 mL ofacetic acid. Following the addition of the H₂SO₄, the flask temperaturewas adjusted to 15° C. The heterogeneous mixture was stirred at thistemperature for 70 min before adding an amount of Ac₂O slowly (SeeTable 1) (3.2 h addition). During the Ac₂O addition, the internalreaction temperature reached 37° C. Following completion of the Ac₂Oaddition, the reaction temperature was increased to 58° C. The reactionmixture became a homogeneous solution 6.8 h after adding the cellulose.The reaction temperature was maintained at 58° C. for an additional 4 hafter the homogeneous solution was obtained. The reaction mixture wasdiluted with 500 mL of acetic acid before pouring slowly with highagitation into 5 L of H₂O. This gave a fine white powder, which wasisolated by filtration and dried.

TABLE 1 Molar eq. Molar eq. Example of formate (amt) of Ac₂O (amt)DS_(F) DS_(Ac) 1 12 (440 gr) 11.5 (835 mL) 1.15 1.85 2 9 (330 gr) 11.5(835 mL) 0.88 2.22 3 6 (220 gr) 11.5 (835 mL) 0.85 2.29 4 2 (73 gr) 11.5(835 mL) 0.49 2.60 5 12 (440 gr) 4.6 (334 mL)FIG. 1 shows the ¹H NMR spectra for Examples 1-4. The resonances due tothe C6 protons of the carbon bearing a formate or acetate substitutentare labeled as 6 F and 6A. This data illustrates that as the number ofequivalents of formic acid increases, the DS of formate and the ratio ofC6 formate/acetate increases. When the concentration of formic acid isheld constant and the amount of Ac₂O is decreased (Example 5), the DS offormate and the ratio of C6 formate/acetate remains virtually unchanged.This data demonstrates that the concentration of formic acid is one ofthe features that control the DS of formate and selectivity at C6 forformate.

Examples 6-8

To a 1 L 3-neck round-bottom flask equipped with a mechanical stirrer,reflux condenser, and addition funnel was added 100 mL of 88% formicacid (15 molar equivalents based on cellulose). The solution was chilledto 0° C. before adding 65 mL of Ac₂O over a 10 min period. After warmingto ambient temperature, 25 g of cellulose was added to the solutionfollowed by a solution of 1.88 g of H₂SO₄ in 15 mL of acetic acid. Theheterogeneous mixture was stirred for 30 min before the flasktemperature was placed in a 30° C. water bath. To the heterogeneousmixture was added 172 mL of Ac₂O (9 molar equivalents based oncellulose, 20 min addition). Following completion of the Ac₂O addition,the reaction mixture was stirred for 10 min before the reactiontemperature was increased to 50° C. The reaction mixture became ahomogeneous solution 1.7 h after adding the cellulose. The reactiontemperature was maintained at 50° C. and aliquots were removed atdifferent time intervals. Each sample was treated with 0.43 g ofMg(OAc)₂ in 6.7 mL of acetic acid before pouring the sample into 5 wt %aqueous acetic acid. This gave a white solid, which was isolated byfiltration, washed thoroughly, and dried. This reaction was repeated 2additional times in which the reaction temperature was increased to 58°C. and to 65° C. following the Ac₂O addition. The results are summarizedin Tables 2, 3, and 4.

TABLE 2 Reaction Reaction Example Temperature Time DS_(F) DS_(Ac) Mn MwMz 6-A 65 1.8 0.9 2.01 37,793 302,194 1,035,582 6-B 65 5.8 0.88 2.0613,730 39,798 98,067 6-C 65 8.8 0.81 2.15 8,233 24,533 76,466 6-D 6523.0 0.52 2.43 3,965 6,293 10,121

TABLE 3 Reaction Reaction Example Temperature Time DS_(F) DS_(Ac) Mn MwMz 7-A 58 1.6 1.01 1.95 28,829 102,342 252,630 7-B 58 5.6 0.95 1.9714,404 38,013 80,493 7-C 58 9.6 0.84 2.06 7,872 18,261 42,562 7-D 5823.6 0.54 2.42 3,685 5,943 10,324

TABLE 4 Reaction Reaction Example Temperature Time DS_(F) DS_(Ac) Mn MwMz 8-A 50 2.7 1.05 1.90 29,688 115,177 285,585 8-B 50 4.7 1.02 1.9327,740 106,452 268,996 8-C 50 5.7 1.06 1.99 27,837 90,314 203,959 8-D 508.7 0.97 2.00 19,772 89,852 262,219 8-E 50 24.8 0.82 2.02 10,912 42,000120,719

In these examples, cellulose acetate formates were prepared usingidentical conditions except for the reaction temperature. Shortly afterobtaining a homogeneous reaction mixture, which is indicative of fullesterification of the cellulose, the first sample was removed andisolated. In each case, cellulose acetate formates were obtained(entries 6-A, 7-A, 8-A) with weight-average molecular weights rangingfrom about 300,000 to about 100,000 and a formate DS from about 0.9 toabout 1.05. The data in Tables 2, 3 and 4 shows the change in molecularweight, formate DS and acetate DS when the reaction is maintained atdifferent temperatures after reaching the triester stage. At 65° C.(Table 2), the formate DS was relatively unchanged at 5.8 h but droppedwith longer reaction times with a corresponding increase in acetate DS.This indicates transesterification can occur with long reaction times atthis temperature. The weight-average molecular weight decreased at 65°C. from 302,000 to 6,200 over the time frame studied. At 58° C., theobservations were very similar. At the 50° C. reaction temperature, theformate DS did not significantly change until after about 24 h. Theweight-average molecular weight also decreased much more slowlyeventually reaching 42,000 after 24.8 h reaction time.

Example 9

To a 5 L 5-neck round-bottom jacked-flask equipped with a mechanicalstirrer, reflux condenser, thermocouple, addition funnel, and atemperature controlled circulating bath was added 500 mL of 88% formicacid (15 molar equivalents based on cellulose). The solution was chilledto 4° C. before adding 430 mL of Pr₂O over a 20 min period. The solutionwas warmed to 20° C. before adding 125 g of water-activated cellulose.To the heterogeneous mixture was added a solution of 9.35 g of H₂SO₄ in80.5 mL of propionic acid. Following the addition of the H₂SO₄, theflask temperature was adjusted to 30° C. before adding 885 mL of Pr₂Oslowly (9 molar equivalents based on cellulose, 30 min addition). Duringthe Pr₂O addition, the maximum internal reaction temperature reached was37° C. The reaction mixture became a homogeneous solution 55 min afteradding the cellulose. The reaction temperature was increased to 50° C.and homogeneous solution was held at this temperature for an additional5 h before adding 2.5 g of Mg(OAc)₂ in 150 mL of propionic acid. Afterfiltration through a 70-100μ glass frit funnel, the clear solution waspoured slowly with high agitation into 5 L of 5 wt % aqueous aceticacid. This gave a white solid, which was isolated by filtration. Afterdrying, 215.2 g of a fine white powder was obtained.

Characterization of this material by ¹H NMR and GPC revealed that theproduct was a cellulose propionate formate with a formate and propionateDS of 1.05 and 1.74, respectively, with a Mw of 120,295. Carbon 13 NMRindicated that majority of the formate was located at C6. A smalleramount of formate was located at C2 and none was found at C3.Correspondingly, most of the propionate was attached at C2 and C3 andonly relatively small amount of propionate was located at C6.

Example 10

To a 5 L 5-neck round-bottom jacked-flask equipped with a mechanicalstirrer, reflux condenser, thermocouple, addition funnel, and atemperature controlled circulating bath was added 500 mL of 88% formicacid (15 molar equivalents based on cellulose). The solution was chilledto 4° C. before adding 325 mL of Bu₂O over a 20 min period. The solutionwas warmed to 20° C. before adding 125 g of water-activated cellulose.To the heterogeneous mixture was added a solution of 9.4 h of H₂SO₄ in75 mL of butyric acid. Following the addition of the H₂SO₄, the flasktemperature was adjusted to 30° C. and 1060 mL of Bu₂O slowly added (8.4molar equivalents based on cellulose, 25 min addition). During the Bu₂Oaddition, the maximum internal reaction temperature reached was 49° C.The reaction mixture became a homogeneous solution 60 min after addingthe cellulose. The reaction temperature was increased to 58° C. and thehomogeneous solution was held at this temperature for an additional 4.3h before adding 2.5 g of Mg(OAc)₂ in 150 mL of butyric acid. Afterfiltration through a 70-100μ glass frit funnel, the clear solution wasdiluted with 1 L of acetic acid and poured slowly with high agitationinto 5 L of H₂O. This gave a white solid, which was isolated byfiltration. After drying, 211.6 g of a fine white powder was obtained.

Characterization of this material by ¹H NMR and GPC revealed that theproduct was a cellulose butyrate formate with a formate and butyrate DSof 1.16 and 1.75, respectively, with a Mw of 49,226. Carbon 13 NMRindicated that majority of the formate was located at C6. A smalleramount of formate was located at C2 and none was found at C3.Correspondingly, most of the butyrate was attached at C2 and C3 and onlyrelatively small amount of butyrate was located at C6.

Example 11

To a 1 L 3-neck round-bottom flask equipped with a mechanical stirrer,reflux condenser, and addition funnel was added 100 mL of 88% formicacid (15 molar equivalents based on cellulose) followed by 65 mL ofAc₂O. To this solution was added 25 g of water-activated cellulosefollowed by a solution of 1.88 g of H₂SO₄ in 15 mL of butyric acid. Tothe heterogeneous mixture was added 334 mL of Bu₂O (13.3 molarequivalents based on cellulose, 45 min addition). Following completionof the Bu₂O addition, the reaction mixture was stirred for 35 min beforethe reaction temperature was increased to 50° C. The reaction mixturebecame a homogeneous solution 9 h after beginning the addition of Bu₂Oto the cellulose. The cellulose ester was isolated by adding thereaction solution to H₂O, filtering and drying.

Proton NMR showed that the product was a cellulose acetate butyrateformate with a DS_(F)=0.98, DS_(Ac)=1.07, and DS_(Bu)=0.92. Theweight-average molecular weight was 46,000.

Example 12

Cellulose acetate formate (10 g, DS_(F)=0.93, DS_(Ac)=2.0) was dissolvedin 120 mL of acetic acid at 60° C. To this solution was added 13.3 mL ofH₂O. Samples were removed at different time intervals and isolated bypouring the sample into H₂O. The white solid was isolated by filtration,washed, and dried before submitting for analysis by ¹H NMR to determinethe formate and acetate DS. The resulting data is summarized in FIG. 2which shows the change in formate DS as a function of time. The initialhydrolysis of formate is rapid but the hydrolysis rate slows with time.Under these conditions, ca. 24 h is required for complete hydrolysis offormate. The ¹H NMR analysis also showed that the acetate DS wasunchanged.

Example 13

A cellulose acetate formate having a DS_(Ac)=1.80 and DS_(F)=0.68 washydrolyzed according to the general procedure of Example 12 for 24 h.Relevant physical properties for this cellulose acetate relative to arandom substituted cellulose acetate produced commercially by EastmanChemical Company as CA320S are presented in Table 5.

TABLE 5 Tg Tm Sample DS_(Ac) RDS₆ RDS₃ RDS₂ Mn Mw Mz ° C. ° C. Example13 1.79 0.31 0.78 0.70 18,197 43,719 92,863 201 236 CA320S 1.79 0.580.57 0.64 21,097 50,450 96,561 208 244

The data in Table 5 shows both of the cellulose acetates have the sameDS_(A), and similar Mw. However, the CA prepared from the CAF has aRDS₆, nearly half of that for CA320S. With CA320S, the RDS at the 3hydroxyls is very close to 1:1:1, which is typical for a randomsubstituted CA. With the CA prepared from CAF, the RDS₆ is much lessthan that observed for the 2 and 3 positions. Comparison of the ¹³C NMRcarbonyl resonances for the two cellulose acetates indicates that the CAprepared from the CAF has more of the 2,3-diacetate monomer than therandom substituted CA.

Example 14

Following the general procedure of Examples 6-8, a cellulose acetateformate was prepared and then, without isolation, hydrolyzed for 24 haccording to the general procedure of Example 12. Relevant physicalproperties for this cellulose acetate relative to a non-selectivelysubstituted cellulose acetate produced commercially by Eastman ChemicalCompany as CA355 are presented in Table 6.

TABLE 6 Sample DS_(Ac) RDS₆ RDS₃ RDS₂ Mn Mw Mz Example 14 2.03 0.38 0.800.86 22,058 84,152 229,224 CA355 2.06 0.69 0.65 0.72 25,365 62,328126,603

The data in Table 6 shows both of the cellulose acetates have nearly thesame DS and similar Mw. However, the CA prepared from the CAF has a RDS₆significantly less than the CA355. With CA355, the RDS at the 3hydroxyls are close to 1:1:1. With the CA prepared from CAF, the RDS₆ ismuch less than that observed for the 2 and 3 positions which is typicalfor a regioselectively substituted cellulose ester prepared by themethods of the present invention. Comparison of the ¹³C NMR carbonylresonances for the two cellulose acetates indicates that the CA preparedfrom the CAF has more 2,3-diacetate than CA355.

Example 15

A cellulose propionate formate having a DS_(Pr)=1.74 and DS_(F)=1.05 washydrolyzed according to the general procedure of Example 12 for 24 h.Proton NMR indicated that the CP had a DS of 1.67. The Mw of this CP was93,420. The Tm taken from the first scan DSC spectra was 229° C. and thesecond scan Tg was 180° C. The RDS at the 6, 3, and 2 positions were0.26, 0.69, and 0.71, respectively, indicating that the CP contained ahigh amount of the 2,3-dipropionate substituted monomer.

Example 16

To a 100 mL 3-neck round bottom flask was added 2 g of a regioselectivesubstituted cellulose acetate with a DS_(Ac)=2.03 prepared according tothe general method of Examples 6-8 and 20 mL of propionic acid. The CAwas stirred at 80° C. until a homogeneous solution was obtained. Aftercooling to 50° C., 2.12 g of propionic anhydride was added followed by0.05 g of H₂SO₄ in 0.5 mL of propionic acid. The reaction mixture wasstirred for 4 h at 50° C. before pouring the solution into water. Theproduct was isolated by filtration, washed with H₂O and dried.

Proton NMR indicated that the product had a DS_(Ac)=1.93 andDS_(Pr)=1.08. The Mw for this CAP was 108,827. Carbon-13 NMR revealedthat most of the propionate was located at the 6 position while themajority of the acetate was located at the 2 and 3 positions.

Example 17

To a 300 mL 3-neck round bottom flask was added 7 g (29.8 mmol) of a CA(prepared according to the general methods of Examples 6-8 and 12) and115 mL of acetic acid. The mixture was stirred at 50° C. until ahomogeneous solution was obtained. To this solution was added 20 mL ofH₂O followed by 317.8 mg (1.49 mmol, 0.05 eq) of NHAcTEMPO and 153.3 mg(1.49 mmol, 0.05 eq) of NaBr, respectively. To this solution was pumped31.3 mL (148.9 mmol, 2.5 eq, 7.2 min/mL) of 32% peracetic acid. Afterthe addition of ca. 4 mL of peracetic acid, the viscosity of thesolution was observed to increase. After adding ca. 7 mL of peraceticacid, the viscosity returned to that at the start of the reaction.Aliquots were removed from the reaction at 4, 5.6, 7.3, and 8.6 h fromthe start of the peracetic acid addition. Each aliquot was poured intocold EtOH and the resulting solid was isolated by filtration, washedextensively with cold EtOH, and dried. Table 7 summarizes thecharacterization of each sample.

TABLE 7 Oxidation of cellulose acetate using 0.05 equivalents ofNHAcTEMPO and NaBr. time Yield Mw/ Examples (h) (%) AN DS_(Ac) Mn Mw MzMn Starting 0 1.68 24,584 55,410 98,037 2.25 Material 17-A 4 92 97.52.00 99,927 426,173 1,000,023 4.26 17-B 5.6 89 88.9 1.94 92,989 372,740868,995 4.01 17-C 7.3 86 108.0 2.02 80,785 343,556 828,377 4.25 17-D 8.685 94.6 1.97 14,382 43,061 114,434 2.99

Example 17-A is the first aliquot taken 4 h after beginning theperacetic acid addition (15 min after completion of the peracetic acidaddition). As can be seen, Example 17-A has an acid number of 97.5, theapparent DS has increased to 2.0, and the observed Mw is now 426,173. Asthe reaction progresses, the acid number and the DS remains relativelyconstant while the Mw decreases reaching 43,061 for Example 17-D. Therelatively constant DS indicates that little or no hydrolysis of theacetyl substitutent is occurring under these reaction conditions.

This example demonstrates that oxidation of cellulose esters can occurrapidly under these reaction conditions without significant hydrolysisof the acyl substitutent. The increase in apparent Mw is believed to bedue to crosslinking resulting from the presence of aldehydes. Thesubsequent decrease in Mw is believed to be due to further oxidation ofthe aldehydes rather than significant chain cleavage.

Examples 18-19

Cellulose acetate (prepared according to the general methods of Examples6-8 and 12) was oxidized according to the general procedure of Example17. Two experiments were conducted that differed only in the reactiontemperature and addition rate of the peracetic acid. The reactionconditions and characterization of the products are summarized in Tables8 and 9.

TABLE 8 Oxidation of cellulose acetate at 40° C., 40° C., 0.1 eqNHAcTEMPO, 0.1 eq NaBr, 2.5 eq PAA, 5.1 h Addition. time Mw/ Example (h)AN DS_(Ac) Mn Mw Mz Mn Starting 0 1.68 24,584 55,410 98,037 2.25Material 18-A 7.42 114.1 2.05 72,004 400,032 1,126,551 5.56 18-B 9.33119.0 2.12 63,013 338,693 937,631 5.38 18-C 11.83 119.3 2.16 51,156252,173 751,184 4.93 18-D 13.92 114.4 2.21 38,036 209,500 644,529 5.51

TABLE 9 Oxidation of cellulose acetate at 60° C., 0.1 eq NHAcTEMPO, 0.1eq NaBr, 2.5 eq PAA, 2.9 h Addition. time Mw/ Example (h) AN DS_(Ac) MnMw Mz Mn Starting 0 1.74 23,758 57,266 106,406 2.41 Material 19-A 2.92121.6 2.10 10,478 45,911 149,928 4.38 19-B 4.5 120.4 2.22 5,706 21,16261,365 3.71 19-C 7 125.7 2.22 4,629 14,437 39,340 3.12 19-D 9.33 120.82.24 4,804 15,328 43,992 3.19

Comparison of the results in Tables 8 and 9 shows that both sets ofreaction conditions led to significant oxidation of the celluloseacetates. At 40° C., oxidation of the cellulose acetate gave acidnumbers only slightly less than that obtained at 60° C. Oxidation ofcellulose acetate at 40° C. gave oxidized cellulose acetates with muchhigher molecular weights. In all cases, the apparent DS remained above2.0 indicating that little, if any, hydrolysis of the cellulose acetatehad occurred.

The ¹H NMR spectra for Example 18-A (7.4 h at 40° C.) and Example 19-A(2.9 h at 60° C.). The presence of a resonance at about 9.5 ppm forExample 18-A, corresponds to that of an aldehyde. This resonance isabsent in the ¹H NMR spectrum for 19-A. Aldehydes in the presence ofalcohols act as cross-linking points via formation of an acetal and canlead to the observed higher molecular weights for the examples in Table8. The absence of an aldehyde resonance in the ¹H NMR spectrum for 19-Aindicates oxidation of aldehyde to carboxy before the aldehyde can crosslink.

The data in Tables 8 and 9 demonstrate that acid numbers above 110 canbe achieved in the reaction temperature range of 40 to 60° C. whilemaintaining reaction times of less than 24 hours. This data in Tables 8and 9 also demonstrates that oxidized cellulose acetates with apparentmolecular weights ranging from 400,000 to 15,000 can be produced. Also,the data on Tables 8 and 9 demonstrates that the amount of aldehydepresent in the polymer can be controlled by selection of reactionconditions.

Examples 20-23

Cellulose acetate (prepared according to the general methods of Examples6-8 and 12) was oxidized at 50° C. according to the general procedure ofExample 17.

TABLE 10 Rate of Eq. addition of Reaction Example Oxidant PAA PAA(min/mL) Time (h) 20 TEMPO (0.1 eq) 2.1 25 6 21 TEMPO (0.1 eq) 6.3 8 722 TEMPO (0.1 eq) 2.1 8 5.5 23 NHAc TEMPO (0.1 eq.) 2.1 25 5.5

FIG. 3 shows the ¹³C NMR C6 carbon resonances for Examples 20-23. Theresonances corresponding to C6 substituted (ca. 63.5 ppm) andunsubstituted (ca. 59 ppm) carbons are indicated. From FIG. 3 it can beseen that oxidation using NHAcTEMPO (Example 23) resulted in almost acomplete loss of the C6 unsubstituted carbon peak through oxidation ofthe C6 unsubstituted carbons. Reactions involving TEMPO (Examples 20-22)resulted in only minor amounts of oxidation of the cellulose acetate.

Examples 24-39

Cellulose acetate (DS=1.79) commercially available from Eastman ChemicalCompany as CA320S was oxidized according to the general procedure ofExample 17 using different primary oxidants. For each entry, thereaction temperature was 50° C. and 1.0 equivalents of peracetic acidwas used as the terminal oxidant. The results of these experiments aresummarized in Table 11.

TABLE 11 Oxidation of cellulose acetate using different primaryoxidants. Primary Eqs Eqs time Ex. Oxidant NHAcTEMPO Oxidant (h) ANDS_(Ac) Mn Mw Mz 24 NaBr 0.075 0.005 7.0 86.0 1.92 82,399 462,6851,273,700 25 NaCl 0.075 0.05 6.1 32.6 44,757 373,245 1,222,505 26 NaOCl0.05 0.05 5.7 77.6 7,962 104,848 425,340 27 Mn(NO₃)₂ 0.05 0.05 6.3 21.91.79 23,676 55,694 105,607 28 Mn(OAc)₃ 0.05 0.05 6 39.8 1.85 21,71681,622 180,797 29 KMnO₄ 0.05 0.05 5.8 69.6 2.11 10,738 55,814 160,774 30KMnO₄ 0 0.05 5.3 15.8 1.99 6,593 100,424 961,709 31 Mn₂O₃ 0.05 0.05 7.538.9 1.79 6,288 28,130 85,789 32 MnO₂ 0.05 0.05 7.4 22.4 1.74 17,19752,593 99,585 33 MgCl₂ 0.05 0.05 7.4 53.8 1.88 104,438 377,680 819,68234 Mg(NO₃)₂ 0.05 0.05 6.0 29.4 1.87 27,120 61,559 115,958 35 FeCl₃ 0.0750.005 6.3 42.9 1.83 56,273 611,843 2,444,184 36 Cu(NO₃)₂ 0.05 0.05 5.39.9 1.81 16,300 49,156 106,042 37 H₂SO₄ 0.05 0.05 5.75 3.6 12,895 59,169205,294 38 Na₂S₂0₅ 0.075 0.005 7.0 3.6 1.74 21,905 55,989 110,453 39Oxone 0.05 0.05 5.2 7.9 1.72 26,699 72,775 181,597

Oxidation of this CA using NaBr as the primary oxidant provided ananionic CA with an acid number of 86 (Example 24). Substitution of NaBrwith other metal halides such as NaCl or NaOCl (Examples 25 and 26) alsoled to significant oxidation of this CA. Salts or acids based on sulfurgave oxidized CA with low acid numbers (Examples 37-39). Example 37 wasparticularly surprising as the prior art teaches that strong acids suchas H₂SO₄ are critical components in TEMPO based oxidations ofpolysaccharides. Examples 27-32 demonstrate that Mn salts are useful asprimary oxidants in the oxidation of polysaccharides such as celluloseesters. That is, it is possible to have halogen free oxidations. Ofparticular interest is Example 28 involving Mn(OAc)₃ which gave an acidnumber of 39.8. In this case, the salt does not contain a halogen.Oxidation of acetate would lead to peracetic acid which, in the absenceof a good primary oxidant, gives only low levels of oxidation. Hence,the observed increase in acid number is due to the Mn. Related to Mn asthe primary oxidant, Examples 29 and 30 are of particular interest.KMnO₄ is a known oxidant of polysaccharides but is also known that highlevels of KMnO₄ are required and that this leads to nonselectiveoxidations with significant loss in molecular weight. Example 29demonstrates that when used with NHAcTEMPO according to the methods ofthe present invention, KMnO₄ can be used catalytically to provide acellulose ester with high levels of oxidation and good molecular weight.In comparison, in the absence of NHAcTEMPO (Example 32), a much loweracid number and molecular weight is obtained. Examples 33-36 demonstratethat other metal salts such as Mg, Cu, and Fe can also be used asprimary oxidants in the oxidation of cellulose esters

This example demonstrates that primary oxidants other than NaBr areuseful in the oxidation of cellulose esters by the methods of thepresent invention. Of particular note is the use of metal salts based onMn, Mg, Fe, and Cu for halogen free oxidations. Also, this example showsthat the presence of a strong acid such as H₂SO₄, is not necessary forthe oxidation of polysaccharide esters as suggested in the prior art. Inthis case, the presence of the strong acid resulted in essentially nooxidation of the cellulose ester.

Examples 40-46

Cellulose acetate (prepared according to the general methods of Examples6-8 and 12) was oxidized according to the general procedure of Example17 using variable amounts of NaBr. In each experiment, the number ofequivalents of NHAcTEMPO was 0.05 eq and the reaction temperature was50° C. The results of these experiments are summarized in Table 12.

TABLE 12 Temp Eqs Eqs time Entry (° C.) PAA NaBr (h) AN DS_(Ac) Mn Mw Mz40^(a) 70 1.75 0 7.4 1.7 1.73 12264 29393 72520 41^(b) 60 1.75 0 6.0 5.81.76 20518 53836 128975 42^(b) 50 1.75 0 5.8 15.5 1.74 19956 50610113075 43^(a) 50 1.0 0.005 7.3 52.0 1.88 33154 240966 901965 44^(a) 501.0 0.010 7.3 68.5 1.91 24985 303643 1076774 45^(a) 50 1.0 0.025 6.484.3 1.94 46358 313329 1029011 46^(b) 50 1.75 0.050 6.0 99.8 2.05 52736712062 1956569 For the starting CA: DS = 1.72, Mw = 34124. For thestarting CA: DS = 1.74, Mw = 57266.

The data in Table 12 illustrates a number of points. First, at areaction temperature of about 50° C. (cf. Examples 40-42), a primaryoxidant is not necessary to obtain oxidation. However, addition of evena small amount of NaBr increased the level of oxidation (cf. Examples 43and 44) relative to when none was used. As the amount of NaBr wasincreased, both the acid number and the molecular weight were observedto increase. The acid number and the molecular weight of the oxidizedcellulose ester can be controlled by varying the amount of NaBr whilemaintaining a constant temperature and concentration of NHAcTEMPO.

Examples 47-49

Cellulose acetate (prepared according to the general methods of Examples6-8 and 12) was oxidized according to the general procedure of Example17 using variable amounts of NHAcTEMPO. In each experiment, the numberof equivalents of NaBr was 0.025 eq and the reaction temperature was 50°C. The results of these experiments are summarized in Table 13.

TABLE 13 Eqs time Examples NHAcTEMPO (h) AN DS_(Ac) Mn Mw Mz 47^(a)0.025 5.8 39.6 1.84 28,439 136,195 491,427 48^(a) 0.050 6.4 84.3 1.9446,358 313,329 1,029,011 49^(b) 0.075 5.8 144.9 2.25 14,034 498,0081,652,295 For the starting CA: DS = 1.72, Mw = 34124. For the startingCA: DS = 1.68, Mw = 55410.

The date in Table 13 for Examples 47-49 shows that as the number ofequivalents of NHAcTEMPO are increased while maintaining a constantamount of NaBr and a constant temperature, the acid number and molecularweight of the products increases.

Examples 50-55

Cellulose acetate propionate and cellulose acetate butyrate,commercially available from Eastman Chemical Co. as CAP504 and CAB553,were oxidized at 50° C. according to the general procedure of Example 17using 1.0 eqs PAA, 0.005 eqs of NaBr, and 0.075 eqs NHAcTEMPO. In thecase of the CAP 504, propionic acid was substituted for acetic acid. Inthe case of the CAB 553, butyric acid was substituted for acetic acid.The oxidized cellulose esters were isolated by precipitation in 5%aqueous acetic acid. The results of these experiments are summarized inTable 14.

TABLE 14 Time Examples Substrate (h) AN DS Mn Mw Mz CAP 0 2.19 9,57222,155 40,845 50 CAP 2.75 46.8 2.46 30,196 183,329 618,702 51 CAP 5.0857.1 2.43 20,139 109,475 350,227 52 CAP 22.67 61.3 2.42 21,761 102,716298,772 CAB 0 2.24 10,786 31,114 63,308 53 CAB 3.08 33.9 2.25 25,717461,098 1,663,635 54 CAB 4.17 43.9 2.28 34,126 312,655 1,036,959 55 CAB22.42 40.7 2.24 24,126 162,815 496,651

The data in Table 14 for the Examples demonstrates that celluloseesters, such as CAP and CAB, can be oxidized according to the methods ofthis invention.

Example 56

Water activated cellulose (10 g) was suspended in 400 g of a mixture ofacetic acid/H₂O (85/15, wt./wt.) containing NHAcTEMPO (0.99 g) and NaBr(0.032 g) at 50° C. The oxidation was started by slowly adding 25.9 mLof a 32% peracetic acid solution with stirring, in 3 hours, to themixture. The oxidized cellulose was isolated, after 4.5 hours ofreaction, by filtration, washed, and dried at 50° C. in a vacuum oven.

The oxidized cellulose was acetylated with acetic anhydride usingsulfuric acid as catalyst. Specifically, oxidized cellulose (10 g) wasactivated with water, dewatered with acetic acid, and then suspended ina mixture of acetic acid (100 g) and acetic anhydride (28 g) at 13-15°C. The esterification was started by adding a mixture of sulfuric acid(0.75 g) and acetic acid (20 g) to the above cold cellulose, acetic acidand acetic anhydride mixture with vigorous mixing. This reaction mixturewas kept at 20 to 23° C. for about 20 to 30 min follow by heating it at50° C. until a viscous solution was obtained. Unreacted acetic anhydridewas destroyed by addition of a water/acetic acid mixture. The acetylatedoxidized cellulose was recovered by precipitation from water after thesulfuric acid used as catalyst was neutralized with sodium acetate.After drying, the acid number of the oxidized CA was found to be 10. Noloss of product due to solubilization (vide infra) was observedsuggesting an even distribution of carboxylates.

Example 57 (Comparative)

Cellulose (Placetate F) was first activated with 10% aqueous NaOH at 0to 10° C. for 10 to 20 min. The NaOH solution was then removed fromcellulose by filtration and washing with distilled water. The pH of thisactivated cellulose was then adjusted to 10.8 to 10.9 using 0.5 M NaOH.The oxidation was started by slowly adding 11.5% solution of NaOCl (85ml) to a mixture of activated cellulose (10 g), TEMPO (0.1 g), NaBr (3.2g) and distilled water (400 g) in a 3-necked round bottle flask withstirring. The reaction temperature was 25° C., and the pH of thereaction mixture was kept at 10.8 to 10.9 with 0.5 M NaOH. Cellulose wasin solution at the end of the addition of NaOCl solution (120 min.). Theoxidized cellulose was recovered by precipitation from ethanol, washedwith ethanol and dry at 50° C. in a vacuum oven. After drying, the acidnumber for the oxidized cellulose was determined to be 133.

The above reaction was repeated with the exception that only 25.5 mL ofNaOCl was utilized. At the end of the contact time, insoluble fiber wasremoved from the reaction mixture by filtration. The soluble cellulosefraction was isolated as above. It was found that 37 wt % of the productwas the soluble portion and 63 wt % of the product was the insolublefiber portion that was removed by filtration. The insoluble cellulosefraction was found to have an acid number of 5.6.

Collectively, this data indicates that the oxidation of cellulose underthese conditions proceeds by oxidation and solubilization of thecellulose from the fiber surface. That is, the reaction is heterogeneousand the distribution of the carboxylates is not random.

Example 58

Commercial cellulose esters (CA320S, CA398-30, CAP504-0.2, CAB 553-0.4)available from Eastman Chemical Company, were oxidized according to themethods described in Examples 17 and 50. The solubility of theseoxidized cellulose esters were evaluated in a variety of solvents bymixing 0.2 g of oxidized cellulose ester in 1.8 g of solvent for ca. 16h. The samples were inspected and graded on the following scale:1=Insoluble; 3=Partially Soluble; 5=Gels; 7=Soluble, Hazy Solution;9=Soluble, Clear Solution. The results are summarized in Table 15. Thesolubility of the non-oxidized commercial cellulose esters in the samesolvents are provided for each sample within the parenthesis.

TABLE 15 Solubility of oxidized cellulose esters in different solvents.Oxidized CA Oxidized CA Oxidized CAP Oxidized CAB DS = 1.94 DS = 2.67 DS= 2.41 DS = 2.16 Solvent AN = 88.7 AN = 51.8 AN = 61.3 AN = 40.7 Formicacid 9 (9) 9 (9) 9 (9) 9 (9) Acetic acid 9 (9) 9 (9) 9 (9) 9 (9) Acetone3 (1) 9 (9) 9 (9) 9 (9) MEK 5 (1) 9 (9) 9 (9) 9 (9) Ethyl acetate 5 (1)7 (5) 9 (9) 9 (9) PM acetate 5 (1) 5 (1) 9 (9) 9 (9) diacetone alcohol 3(1) 3 (9) 9 (9) 9 (9) MPK 3 (1) 3 (1) 9 (3) 9 (9) EB 5 (1) 3 (1) 9 (9) 9(9) EP 5 (1) 3 (1) 9 (9) 9 (9) PM 3 (1) 3 (1) 9 (9) 9 (9) PB 5 (1) 3 (1)9 (9) 9 (9) Methanol 3 (1) 1 (1) 9 (9) 9 (9) Methyl acetate 3 (3) 9 (1)9 (9) 9 (9) Propionic acid 5 (1) 1 (3) 9 (9) 9 (9) Isopropyl acetate 3(1) 1 (1) 3 (3) 5 (9) EB acetate 3 (1) 1 (1) 7 (3) 5 (9) PP 3 (1) 1 (1)1 (1) 5 (9) n-Propyl acetate 5 (1) 1 (1) 3 (3) 5 (9) Isobutyl acetate 3(1) 1 (1) 3 (1) 5 (1) Texanol 3 (1) 1 (1) 3 (1) 5 (9) 2-EH acetate 1 (1)1 (1) 1 (1) 1 (1) Dichloromethane 1 (1) 1 (9) 1 (7) 7 (9) EEP 1 (1) 1(1) 7 (3) 9 (9) MIBK 1 (1) 1 (1) 7 (3) 7 (9) MAK 1 (1) 1 (1) 3 (1) 3 (9)n-Butyl acetate 1 (1) 1 (1) 3 (3) 3 (9) IBIB 1 (1) 1 (1) 1 (1) 1 (1)

This reveals that oxidized cellulose esters are soluble in a widevariety of solvents typically utilized in many coating applications. Asthe data indicates, solubility is dependent upon the type ofsubstituent, DS, and acid number.

Example 59

Two samples of a regiospecific substituted cellulose acetate (DS=1.72)prepared according to the general methods of Examples 6-8 and 12, wereoxidized according to the general procedure of Example 17. Forcomparison, two samples of a randomly substituted cellulose acetatehaving virtually the same DS (1.79) were also oxidized by the method ofExample 17. In each experiment, the number of equivalents of NHAcTEMPOwas 0.075 eq, the number of equivalents of NaBr was 0.005, the number ofequivalents of PAA was 1.0, the reaction temperature was 50° C., and thereaction times were ca. 8 h. The acid numbers for the two oxidizedregioselective substituted cellulose acetates were 109 and 104. The acidnumbers for the two randomly substituted cellulose acetates were 79 and86.

This example demonstrates that at the same degree of substitution, aregioselectively substituted cellulose ester can provide an oxidizedcellulose acetate with a higher acid number than that obtained from theequivalent randomly substituted cellulose acetate.

Example 60

Cellulose acetate (42.8 mmol, DS=1.79 was dissolved in 100 mL of glacialacetic acid and 20 mL of water. After warming to 50° C., 0.02 eqMn(NO₃)₂, 0.02 eq Cu(NO₃)₂, and 0.104 eq TEMPO were added, respectively.The reaction was stirred at 50° C. open to the atmosphere. Approximately4 h after adding the TEMPO, the viscosity of the solution increaseddramatically. In order to decrease the viscosity of the reactionsolution, 32 mL of 75% aqueous acetic acid was added.

After 23 h of reaction time, the reaction mixture was poured into anOmni blender and a mixture of H₂O and ice was added. After mixing, theoxidized CA precipitated. The product was washed twice with water beforewashing with ethanol. Drying in vacuo at 60° C. for 65 h gave a whitesolid (84% yield). After drying, the product was quite difficult todissolve in most solvents due to cross-linking via acetal formationbetween the newly formed aldehyde and unreacted hydroxyls that arepresent in the cellulose ester. Nevertheless, the ¹H NMR of the product(DMSO-d₆, reveals the resonances due to the desired aldehyde groups(9-10 ppm). The resonances centered near 6 ppm are believed to be due toacetals formed by reaction of unreacted hydroxyls with the aldehydefunctionality.

A portion (8.6 mmol) of the oxidized cellulose acetate prepared abovewas dissolved in 20 mL of glacial acetic acid and 13 eq of benzyl amine.To this solution was added 0.4 g of 10% Pd/C before heating the solutionto 40° C. The solution was then blanketed with a positive hydrogenatmosphere.

After 21 h, the reaction mixture was filtered to remove the Pd/C. Thesolution was then poured into water which was maintained at 0° C.overnight. The product was isolated by filtration, washed, and dryed invacuo at 60° C. for 16 h (yield=44%).

A ¹H NMR spectrum of the product was used to calculate the apparent DSfor acetate of 2.14 and the apparent DS for amine of 0.60. Quantitativecarbon 13 NMR also confirmed successful introduction of benzyl amine.This is demonstrated by the presence of resonances due to aromaticcarbons (cf. 122-140 ppm) and resonances due to CH₂ attached to NH (cf.44-50 ppm).

Example 61

Cellulose Acetate (240 g, 1.03 mol, DS=1.79) was oxidized according tothe method described in Example 60. At the conclusion of the reaction,the oxidized cellulose acetate was isolated by precipitation in coldMeOH. The product was isolated by filtration, washed with MeOH, andstored wet in MeOH. To determine the solids present and to obtain ananalytical sample, a portion was removed and dried at 60° C. in vacuo.The product was found to contain 68.5 wt % MeOH.

Methanol wet oxidized cellulose acetate (6.35 g, 8.6 mmol) was dissolvedin benzyl amine (25 eq) and glacial acetic acid (82 mL). The MeOH wasremoved by bubbling N₂ through the solution. After all of the MeOH wasremoved, 0.4 g of 10% Pd/C was added to the solution and the solutionwas placed under a positive H₂ atmosphere. The reaction was stirred at25° C. for 16 h before venting the hydrogen. The Pd/C was removed bycentrifuging and decanting the liquids. Approximately 70% of the aceticacid was removed in vacuo before cold water was added to precipitate thecellulose acetate benzyl amine. The product was isolated by filtration,washed, and dried at 60° C. in vacuo. Analysis of this material byproton NMR revealed that the apparent DS acetate was 1.73 and theapparent DS amine was 0.26. GPC indicated that the product had aweight-average molecular weight of 22,700.

Example 62 Preparation of Cellulose Acetate Butyrate Esters Having aHydroxyl Content of 1.42 and Oxidation to an Oxidized CAB

Hydrolysis of Cellulose Esters to Produce Randomly Substituted CelluloseEsters with High Hydroxyl Content:

-   -   To a 12 L 5-neck jacketed round bottom flask equipped with a        mechanical stirrer, a reflux condenser, a recirculation bath for        temperature control, and an addition funnel was added 2410.5 g        of glacial acetic acid, 2140.0 g of butyric acid, 1190.0 g of        deionized water, and 1260.1 g of cellulose acetate butyrate        (CAB381-20, Eastman Chemical Company) with slow stirring.        Following addition of the CAB381-20, the temperature was        increased to 70-71° C. and the mixture was allowed to stir until        a homogenous solution was obtained. To this mixture was added 19        g of sulfuric acid in 100 g of glacial acetic acid. After        addition of the sulfuric acid mixture, the reaction mixture was        held at 70° C. for the entire reaction time. After 12 h reaction        time, 240 g of deionized water was added. After 24 h reaction        time, an additional 400 g of deionized water was slowly added.        After 36 h reaction time, a final addition was added consisting        of 1560.0 g of acetic acid, 72.0 g of butyric acid, and 324.0 g        of deionized water, and 152.8 g of magnesium acetate        tetrahydrate. For characterization purposes, a small portion of        the resulting CAB was isolated by adding the reaction solution        to deionized water, filtering, and washing the solid with water        and drying. The remaining CAB reaction mixture was drained from        the flask and stored at 10° C. until used in oxidation        reactions. Proton NMR indicated that the isolated product had a        DS_(Bu)=1.13, DS_(Ac)=0.44, and DS_(OH)=1.42 DS_(OH). The        weight-average molecular weight (GPC) was 104,681.    -   Oxidation of randomly substituted cellulose esters with high        hydroxyl content: Six oxidation experiments were performed on        the CAB produced above by the general procedure of example 17.        Two different types of primary oxidants were utilized at three        different concentrations at a fixed concentration of NHAcTEMPO        (0.075 eq). The results for these experiments are shown in Table        16.

TABLE 16 Oxidation of randomly substituted cellulose esters usingdifferent primary oxidants and oxidant equivalents. Reaction NaBrMn(OAc)₃ Acid Weight- Sample Time (min) (eqs) (eqs) Number Average MW 11200 0.075 0 98 6103 2 1200 0.01 0 92 5258 3 1200 0.05 0 90 7095 4 12120 0.01 23 35360 5 1200 0 0.05 11 36437 6 1176 0 0.1 72 9539

-   -   This example demonstrates that cellulose esters such as CAB can        be hydrolyzed in acidic aqueous media to produce randomly        substituted cellulose esters with high hydroxyl content.        Oxidation of this CAB using different primary oxidants produced        oxidized CAB with a range of acid numbers (11 to 98) and        weight-average MW (ca. 5000 to 36000). Thus, by selection of        appropriate reaction conditions a broad range of oxidized CAB        can be produced.

Example 63 Preparation of Cellulose Acetate Butyrate Ester Having aHydroxyl Content of 1.81 and Oxidation to an Oxidized CAB

Hydrolysis of Cellulose Esters to Produce Randomly Substituted CelluloseEsters with High Hydroxyl Content:

-   -   The procedure of Example 62 was used to produce a CAB381 having        a high hydroxyl content. This example is different in that the        reaction temperature was maintained at 71° C. and the        composition of the liquids added at 36 h was 990 g of acetic        acid, 48 g of butyric acid, and 560 g of deionized water, and 51        g of magnesium acetate tetrahydrate. For characterization        purposes, a small portion of the resulting CAB was isolated by        adding the reaction solution to deionized water, filtering, and        washing the solid with water and drying. The remaining CAB        reaction mixture was drained from the flask and stored at 10° C.        until used in oxidation reactions. Proton NMR indicated that the        isolated product had a DS_(Bu)=0.96, DS_(Ac)=0.22, and        DS_(OH)=1.81 DS_(OH). The weight-average molecular weight (GPC)        was 66,097.        Oxidation of Randomly Substituted Cellulose Esters with High        Hydroxyl Content:    -   The CAB produced above was oxidized by the general procedure of        Example 17 using 0.075 eq of NHAcTEMPO and 0.75 eq of sodium        bromide. The product obtained had an acid number of 104 (mg        KOH/g) and a weight-average molecular weight of 4847.    -   This example demonstrates that CAB can be hydrolyzed in acidic        aqueous media to produce a randomly substituted CAB with high        hydroxyl content. Oxidation of this CAB using 0.75 eqs of NaBr        produced an oxidized CAB with a high acid number and a low        weight-average molecular weight.

Example 64 Solubility of Oxidized Cellulose Esters

The solubility of several oxidized cellulose esters were evaluated todetermine solubility in solvents commonly utilized for coatingsapplications. Samples were prepared at 10% solids by weight and weredesignated as soluble (S), soluble with some gels (SG), partiallysoluble (PS), or insoluble (I). From this example (Table 17), it may beseen that both the composition of the ester substituents and the acidnumber of the polymers influence solubility.

TABLE 17 Solubility of cellulose ester interpolymers in coatingsolvents. Oxidized Oxidized Oxidized Oxidized cellulose cellulosecellulose cellulose acetate acetate acetate acetate propionate butyratebutyrate Solvent (AN = 89) (AN = 69) (AN = 12) (AN = 104) Ethyleneglycol I S I S monobutyl ether Acetone I S I S Methyl ethyl S S I Iketone Methanol I S S S Butyl acetate I SG I S Ethylene glycol I SG I Imonobutyl ether acetate Propylene SG S I S glycol monomethyl etheracetate

Example 65 Preparation of Waterborne Solutions of Oxidized Cellulosics

A typical waterborne cellulose ester such as carboxymethyl celluloseacetate butyrate (Eastman Chemical, CMCAB) may be solubilized in waterusing a combination of solvent, water, and amine. As the proportion ofsolvent in the aqueous solution of cellulose ester increases at constantsolids content, the viscosity of the solution decreases. It wasdetermined that an aqueous solution of oxidized cellulose acetatebutyrate (acid number=104) prepared at 10% solids with 100%neutralization of the acid functionality with dimethylethanolamine(Aldrich) was directly soluble in water and low in viscosity without theneed for additional solvent. In this example, 5.4 grams of deionizedwater was combined with 0.6 grams of oxidized cellulose acetate butyrateand 0.099 grams of dimethylethanol amine and allowed to roll overnightto yield a clear, very light yellow solution with low viscosity.

Example 66 Drug Dissolution from Tablets Consisting Oxidized CelluloseAcetate

Oxidized cellulose acetate (3.7 g, acid number=88) and 1.5 g NF aspirinwere milled in a SPEX liquid nitrogen freezer mill for 6 minutes at 75%maximum speed. Magnesium stearate powder (0.04 g) which had beendispersed in carbon black (0.13 g carbon black to 1.0 g magnesiumstearate) was added to the powder and mixed until an even pale graycolor was achieved. Tablets (0.34-0.37 g) were pressed individuallyusing a tablet press at 5000 psi. Likewise, 6.0 g of cellulose diacetate(CA-398-30) powder was milled with 1.5 g NF Grade aspirin with 0.04 g Mgstearate/carbon black added. Tablets (0.32-0.37 g) tablets were alsopressed at 5000 psi.

The dissolution test was completed using a USP #2 calibrated apparatuswith Teflon paddles. Buffer solutions were degassed at 41° C. through a0.45 micron nylon filter and held under vacuum for an additional 5minutes. After adding the solutions to the dissolution vessels, thesolutions were held at 37.3° C. for 30 minutes to achieve constanttemperature. The tablets were added to 900 ml of USP 1.2 pH buffer or to900 ml of USP pH 6.8 buffer. The tablets were weighted down with aVarian 3-pronged capsule weight. At the beginning of each experiment,the tablets were allowed to sink to the bottom of the 1000 ml vessel,the stirrers were turned on at 50 rpm and samples taken as a function oftime, using polypropylene syringes. The samples were filtered through0.45 micron filters and immediately analyzed for the amount of aspirinin the solution using a Varian UV-Vis Spectrophotometer and quartzabsorption cells. The wavelengths for measuring the amount of salicylicacid at pH 1.2 and 6.8 was 278 nm and 235, respectively. Each set ofexperiments had appropriate standards for reference for quantitativeanalysis.

During the first hour of the experiments, the oxidized cellulose acetate(CAOX) tablets formed cracks at pH 1.2 but retained their original shapeat pH 6.8. After 3 hours, the CAOX tablets in pH 6.8 buffer solution hadalmost completely disappeared leaving a clear solution. At pH 1.2, theCAOX tablets retained the same shape that they had achieved after 10minutes in the buffer solution. In contrast to both, the CA-398-30tablets did not change shape through the course of the experiment at pH1.2 or pH 6.8.

FIG. 5 summarizes the results of these experiments. After 200 min at pH1.2, only 23% of the maximum amount of aspirin had been released fromthe intact CAOX tablets. In contrast, at pH 6.8 84% of the maximumavailable aspirin was released into the media. In the case of the CA398tablets, 27% and 45% of the available aspirin was released at 200 min atpH 1.3 and 6.8 respectively. This illustrates that the CAOX has lowsolubility at pH 1.2 and is sufficiently hydrophobic to preventsignificant release of the highly water soluble aspirin by diffusion. AtpH 6.8, the CAOX dissolved releasing the drug from the matrix. Incontrast, the tablets made from cellulose acetate remained intact atthis pH 6.8 and only 45% of the drug was released by a diffusioncontrolled process.

This example illustrates that the oxidized cellulose esters of thepresent invention can be used to form tablets by compression molding.Because the tablet structure is sensitive to pH, lowered amounts of thedrug is released at pH 1.2 (normal stomach pH) while at higher pH (thenormal pH gradient of the small intestine is 4.5-7.2), high amounts ofthe drug is released. This type of formulation is particularly useful inproviding controlled release of drug actives in the intestine as opposedto the harsh environment of the stomach. That is, the oxidized celluloseesters of this invention act as release rate modifiers.

Example 67 Oxidized Cellulose Acetate Blends with Poorly Water-SolubleDrugs

A solution of oxidized cellulose acetate (acid number=88) was preparedby adding 400 mg of CA to 15 g of pH 4.8 0.1 N citrate buffer. Theheterogeneous mixture was mixed well before carefully adjusting the pHwith 0.1 N NaOH until the CA dissolved giving a clear solution. The pHof the aqueous CA solution was found to ca. 3.8. Four independentaqueous CA solutions were prepared by this process. Concurrently,independent solutions containing 40-41 mg of ritonavir, anastrozole,tamoxifen, or letrozole were prepared by dissolving each drug in 5 mL ofabsolute ethanol. Each of these drugs has poor water solubility. Theethanol solution of each drug was then added slowly to the aqueous CAsolutions previously prepared. After addition of each drug solution, thepH of each solution was measured and found to be 4.0-4.3. The oxidizedCA:drug solutions were then freeze dried which provided white powders ofeach mixture.

Solutions of each of the oxidized CA:drug mixtures were prepared inMillipore water (23.0-26.5 g/L). All of the samples were filtered thru0.45 micron syringe filters before measurement. The pH of each solutionafter filtration ranged from 3.9-4.1. Solutions of each of the oxidizedCA:drug mixtures were also prepared in 50/50 ethanol/Millipore water.All of the oxidized CA:drug mixtures dissolved in the ethanol/watermixture providing clear solutions thus allowing determination of themaximum amount of drug that can be observed with each sample. Allsamples were immediately analyzed for the amount of drug in the solutionusing an UV-Vis Spectrophotometer. The results are summarized in Table18 which gives the % drug solubilized based on the maximum amountpossible when the oxidized CA:drug mixture was redissolved in water.Also given is the ratio of the amount of drug solubilized (Sw) to theintrinsic solubility of the drug (So).

TABLE 18 Solubilization of poorly water-soluble drugs with celluloseester interpolymers. % Drug Sw (g/L/25 Solubi- g of So Drug pKa Druglized drug: CAOX) (g/L) Sw/So (calculated) ritonavir 28 0.5360 0.021824.6 3.48, 11.5 anastrozole 90 1.2481 0.6500 1.9 4.78 tamoxifen 891.1215 0.0006 1869 8.69 letrozole 7 0.1461 0.1200 1.2 3.63

The results summarized in Table 18 illustrate a number of useful points.With this set of conditions, 28% of the ritonavir in the pharmaceuticalformulation was solubilized when dissolved in water which represents a24.6 fold increase in ritonavir solubility when measured in the absenceof the oxidized cellulose acetate. In the case of anastrozole, the %drug solubilized was 90% while Sw/So was 1.9. With tamoxifen, % drugsolubilized was 89% and Sw/So was 1869. For tamoxifen, this dataillustrates that the oxidized CA was both efficient in solubilizing thedrug while providing a very significant increase in tamoxifensolubility. In the case of letrozole, the efficiency (7% drugsolubilized) and Sw/So (1.2) were relatively low.

Also shown in Table 18 are the pKa for each of these basic drugs. Oneshould note, that with ritonavir and letrozole, the pH of theformulations and of the aqueous drug solutions were above the pKa of thedrug. That is, these basic drugs were not significantly ionized. Forboth of these drugs, the % drug solubilized was relatively low. In thecase of anastrozole, the pH of the formulation and of the aqueous drugsolution were very near the pKa of anastrozole. In this case the % drugsolubilized is high while Sw/So is relatively low. With tamoxifen, thepH of the formulation and of the aqueous drug solution is ca. 4.6 unitsless than the pKa of tamoxifen. As noted for tamoxifen, the % drugsolubilized and Sw/So are large. Based on the well knownHenderson-Hasselbalch equation, one can obtain the followingrelationship for the basic drugs of this example:S_(total)=S_(intrinsic)(1+10^((pKa-pH))) Therefore, based strictly onthe concentration of ionized and unionized form of the drugs, the totalsolubility is equal to twice the intrinsic solubility when theformulation pH and drug pKa or ca. equivalent. This is what is observedwith anastrozole (Sw/So=1.9). For each unit difference between the drugpKa and the formulation pH, the total drug solubility changes by anorder of magnitude. In the case of tamoxifen, this is reflected in both% drug solubilized and the large value of Sw/So. In the case ofritonavir, the pKa is less than that the pH media and contribution ofthe ionized species to the total solubility is small but Sw/So isrelatively large. This observation suggests that specific drug:oxidizedcellulose acetate interactions, eg. hydrogen bonding, are alsocontributing to the total solubility. In the case of letrozole, the pKais also less than that the pH media and the low Sw/So value indicatespoor interactions between the drug and the oxidized cellulose acetate.

This example demonstrates that when properly formulated, the celluloseester interpolymers of the present invention can serve to modify thesolubility of drugs in aqueous media. Without wishing to be bound bytheory, it is believed that the cellulose ester interpolymers modifiesthe solubility of drugs by changing the concentration of the ionizedspecies and through specific interactions between the drug and oxidizedcellulose ester interpolymer.

Example 68 Drug Dissolution from Capsules Coated with Oxidized CelluloseAcetate

Topac Inc. gelatin capsules (#3, 0.30 ml) with a lock-ring design werefilled with approximately 0.17-0.19 g USP grade pure aspirin. Thecapsules were then dip-coated 3 times with either a cellulose acetatesolution (2 g CA398-10 NF, 0.22 g DEP, 20 g acetone, 0.10 g charcoalcolorant) or an oxidized cellulose acetate solution (2 g oxidizedcellulose acetate (AN=88), 0.22 g DEP, 18 g acetone, 2 g de-ionizedwater, 0.10 g charcoal colorant) or left uncoated. Charcoal powder wasused as a colorant to determine whether or not the capsules were beingevenly coated. The coated capsules were allowed to air dry overnight.

The dissolution test was completed using a USP #2 calibrated apparatuswith Teflon paddles. Buffer solutions were degassed at 41° C. through a0.45 micron nylon filter and held under vacuum for an additional 5minutes. After adding the solutions to the dissolution vessels, thesolutions were held at 37.3° C. for 30 minutes to achieve constanttemperature. The capsules were added to 900 mL of USP 1.2 pH buffer orto 900 mL of USP pH 6.8 buffer. The tablets were weighted down with aVarian 3-pronged capsule weight. At the beginning of each experiment,the tablets were allowed to sink to the bottom of the 1000 mL vessel,the stirrers were turned on at 50 rpm and samples taken as a function oftime, using polypropylene syringes. The experiment was run continuouslyfor 21 hours. The samples were filtered through 0.45 micron filters andimmediately analyzed for the amount of aspirin in the solution using aVarian UV-Vis Spectrophotometer and quartz absorption cells. Thewavelengths for measuring the amount of aspirin acid at pH 1.2 and 6.8were 280 nm and 298 nm, respectively. Each set of experiments hadappropriate standards for reference for quantitative analysis.

The capsules coated with CA398-10 did not appear to physically changeduring the course of the experiment. As illustrated in FIG. 6, less than2% of the aspirin dissolved at both pH 1.2 and pH 6.8 over the course ofthe experiment. After 300 min at pH 1.2 and 6.8, less than 0.1% of theavailable aspirin was released into the media.

Different results were obtained with the capsules coated with oxidizedcellulose acetate depending on the pH of the experiment. At pH 1.2, theoxidized cellulose acetate coated capsule did not appear to physicallychange. After 300 min at pH 1.2, less than 10% of the maximum amount ofaspirin had been released from the intact coated capsules. At pH 6.8,the oxidized cellulose acetate coated capsule behaved identically to theuncoated capsule at pH 6.8 (FIG. 6). Visually, by 15 minutes, theoxidized cellulose acetate coating had completely disappeared and thegelatin capsule was significantly dissolved. After 300 min at pH 6.8,65% of the maximum available aspirin was released into the media,precisely the amount of the uncoated capsule.

This example demonstrates the use of oxidized cellulose interpolymers asan enteric coating to prevent drug dissolution at pH 1.2 (pH of thestomach) while permitting rapid drug release at the normal pH of thesmall intestine (4.5-7.2). Because the capsule coated with the celluloseester interpolymer is sensitive to pH, lowered amounts of the drug isreleased at normal stomach pH while at intestinal pH, high amounts ofthe drug is released. That is, the cellulose ester interpolymers of thisinvention function as enteric coatings.

Example 69

A solution of oxidized cellulose acetate (acid number=88) was preparedby adding 400 mg of CA to 15 g of pH 4.8 0.1 N citrate buffer. Theheterogeneous mixture was mixed well before carefully adjusting the pHwith 0.1 N NaOH until the CA dissolved giving a clear solution. The pHof the aqueous CA solution was found to ca. 3.8. Four independentaqueous CA solutions were prepared by this process. Concurrently,independent solutions containing 40-41 mg of ritonavir, anastrozole,tamoxifen, or letrozole were prepared by dissolving each drug in 5 mL ofabsolute ethanol. Each of these drugs has poor water solubility. Theethanol solution of each drug was then added slowly to the aqueous CAsolutions previously prepared. After addition of each drug solution, thepH of each solution was measured and found to be 4.0-4.3. The oxidizedCA:drug solutions were then freeze dried which provided white powders ofeach mixture.

Solutions of each of the oxidized CA:drug mixtures were prepared inMillipore water. Sufficient oxidized CA:drug mixture was added so thatthe expected drug concentration was 12-125 mg/L. The pH of each solutionranged from 4.2-5.7. In the case of ritonavir, the sample was filteredthru 0.45 micron syringe filter before measurement. No filtration wasrequired for the other samples (clear solutions with no visible solids).The samples were immediately analyzed for the amount of drug in thesolution using an UV-Vis Spectrophotometer.

FIG. 7 summarizes the results obtained in this experiment

Example 70

Waterborne Coating Formulation containing an oxidized Cellulose Ester ofthe invention was prepared as described below;

Maincote HG-56 w/2.5% Oxidized CAB Grams Grind: DPM 3.6 Dow ChemicalWater 7 Tamol 165 1.9 Rohm & Haas Ammonia (28%) 0.2 Triton CF-10 0.3Rohm & Haas * 15% Oxidized CAB Solution 8.716 Tego 1488 0.3 Tego ChemieTi-Pure R706 39 DuPont Cowles Grind to 7+ Hegman, then add at low speed:Water 1 62.016 Letdown: Maincote HG-56 104.6 Rohm & Haas Ammonia (28%)0.8 Premix then add: DPnB 11 Dow Chemical Water 17 Dibutyl Phthalate 2.8Eastman Chemical Tego 1488 0.5 Tego Chemie Sodium Nitrite 1.8 AcrysolRM-8W 0.6 Rohm & Haas 201.116 * Oxidized CAB sample from Example 63 wasdispersed in 8 grams Eastman EB Solvent/77 Grams of Water giving 15%solids with DMEA to pH 8

The resulting formulation was tested for sag resistance using ASTMD4400-898. The paint showed significantly improved sag resistancerelative to a control which did not contain the oxidized celluloseester. (CAB refers to cellulose acetate butyrate available from EastmanChemical Company).

While the invention has been described with reference to preferredembodiments and working examples, it is to be understood that variationsand modifications may be resorted to as will be apparent to thoseskilled in the art. Such variations and modifications are to beconsidered within the purview and scope of the invention as defined bythe claims appended hereto.

We claim:
 1. A cellulose ester interpolymer comprising anhydroglucoseunits

wherein R₁, R₂, R₃, R₄, and R₅ are independently selected from the groupconsisting of C₂-C₁₂ acyl groups; and, X is hydroxymethylene; whereinthe anhydroglucose units A and B comprise greater than 65% of the totalanhydroglucose units of the cellulose portion of the cellulose esterinterpolymer, and the degree of substitution per anhydroglucose unit ofC₂-C₁₂ acyl groups is from about 1.5 to about 2.5.
 2. The celluloseester interpolymer of claim 1, wherein anhydroglucose units A and Bcomprise greater than 70% of total anhydroglucose units of the celluloseester interpolymer.
 3. The cellulose ester interpolymer of claim 1,wherein anhydroglucose units A and B comprise greater than 80% of totalanhydroglucose units of the cellulose portion of the cellulose esterinterpolymer.
 4. The cellulose ester interpolymer of claim 1, whereinanhydroglucose units A and B comprise greater than 90% of totalanhydroglucose units of the cellulose portion of the cellulose esterinterpolymer.
 5. The cellulose ester interpolymer of claim 1, whereinthe degree of substitution of C₂-C₁₂ acyl groups is from about 1.7 toabout 2.3, and having a weight average molecular weight of at least5,000 g/mol.
 6. The cellulose ester interpolymer of claim 1, having adegree of polymerization of at least
 10. 7. The cellulose esterinterpolymer of claim 1, having a degree of polymerization of at least25.
 8. A cellulose ester interpolymer having a degree of substitutionper anhydroglucose unit of formate of 0.5 to 1.3, and a degree ofsubstitution of C₂-C₁₂ acyl of 1.5 to 2.5.
 9. The cellulose esterinterpolymer of claim 8 having a degree of substitution peranhydroglucose unit of formate of 0.7 to 1.2, and a degree ofsubstitution of C₂-C₁₂ acyl of 1.8 to 2.3.
 10. The cellulose esterinterpolymer of claim 8 having a degree of substitution peranhydroglucose unit of formate of 0.9 to 1.1, and a degree ofsubstitution of C₂-C₁₂ acyl of 1.9 to 2.1.
 11. The cellulose esterinterpolymer of claim 8, wherein at least 70% of the totalanhydroglucose units of the cellulose ester interpolymer are selectedfrom the group consisting of a 6-O-formate-2,3-O—C₂-C₁₂ acyl substitutedanhydroglucose unit and a 2,3,6-O—C₂-C₁₂ acyl substituted anhydroglucoseunit.
 12. The cellulose ester interpolymer of claim 8, wherein at least80% of the total anhydroglucose units of the cellulose esterinterpolymer are selected from the group consisting of a6-O-formate-2,3-O—C₂-C₁₂ acyl substituted anhydroglucose unit and a2,3,6-O—C₂-C₁₂ acyl substituted anhydroglucose unit.
 13. The celluloseester interpolymer of claim 8, wherein at least 90% of the totalanhydroglucose units of the cellulose ester interpolymer are selectedfrom the group consisting of a 6-O-formate-2,3-O—C₂-C₁₂ acyl substitutedanhydroglucose unit and a 2,3,6-O—C₂-C₁₂ acyl substituted anhydroglucoseunit.
 14. The cellulose ester interpolymer of claim 8, having a weightaverage molecular weight of at least 5,000 g/mol.